5-substituted 1,1-dioxo-1,2,5,-thiadiazolidin-3-one derivatives

ABSTRACT

Compounds of the formula 
                         
provide pharmacological agents which are inhibitors of PTPases, in particular, the compounds of formula I inhibit PTP-1B and TC PTP, and thus may be employed for the treatment of conditions associated with PTPase activity. The compounds of the present invention may also be employed for inhibition of other enzymes with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula I may be employed for prevention or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels. The compounds of the present invention may also be employed in the treatment, prevention or control of a number of conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.

This application claims the benefit of U.S. provisional application No.60/369,930, filed Apr. 3, 2002 and U.S. provisional application No.60/369,779, filed Apr. 3, 2002, the contents of which are incorporatedherein by reference.

The present invention provides compounds of the formula

wherein

R₁ is hydrogen, halogen, hydroxy, alkoxy, carboxy, cyano, nitro,trifluoromethyl, alkynyl, alkylthio, heteroaralkyl, heteroaralkoxy orheteroaryloxy provided that R₁ is located at the 2-position when L₃ is—(CHR)_(s)— in which s is zero; or

R₁ is optionally substituted alkyl, alkenyl, optionally substitutedamino, aralkyl, aralkoxy, aralkylthio, aryloxy, arylthio or cycloalkylprovided that a monocyclic aryl group which is substituted at the paraposition with a methylene or ethylene bridged nitrogen containingheterocycle does not constitute part of R₁ when

-   -   (i) R₁ is located at the 2-position and L₃ is —(CHR)_(s)— in        which s is zero;    -   (ii) X and Y each are CH; and    -   (iii) Q₂ is oxygen; or

C—R₁ may be replaced with nitrogen or N→O; or

R₁ and R₂ combined together with the carbon atoms to which R₁ and R₂ areattached form an optionally substituted fused 5- to 6-membered aromaticor heteroaromatic ring provided that R₁ and R₂ are attached to carbonatoms adjacent to each other; or

R₂ is hydrogen, halogen, hydroxy, alkoxy, cyano, trifluoromethyl, nitro,optionally substituted amino, optionally substituted alkyl, alkylthio,aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkylthio, aryloxy,heteroaryloxy, arylthio or cycloalkyl; or

R₂ is —C(O)R₃ wherein

-   -   R₃ is hydroxy or optionally substituted alkoxy; or    -   R₃ is —NR₄R₅ in which R₄ and R₅ are independently hydrogen,        optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,        aryl, heterocyclyl, aralkyl or heteroaralkyl;

L₁ is a single bond; or

L₁ is carbon which combined together with R₂ and the carbon atoms towhich L₁ and R₂ are attached form an optionally substituted fused 5- or6-membered aromatic or heteroaromatic ring provided that L₁ and R₂ areattached to carbon atoms adjacent to each other; or

L₁ is CH or nitrogen which taken together with R₂ and the carbon atomsto which L₁ and R₂ are attached form a fused 5- to 7-membered ring whichmay be interrupted with one or two heteroatoms selected from oxygen,nitrogen and sulfur provided that L₁ and R₂ are attached to carbon atomsadjacent to each other; or

L₁ is CH, oxygen, sulfur or nitrogen and L₂ is carbon which combinedtogether with L₁, R₂ and the carbon atoms to which L₁ and R₂ areattached form an optionally substituted fused 5- or 6-membered aromaticor heteroaromatic ring provided that L₁ and R₂ are attached to carbonatoms adjacent to each other; or

L₁ is —CH₂—, oxygen, sulfur or —NR₆— and L₂ is CH which taken togetherwith L₁, R₂ and the carbon atoms to which L₁ and R₂ are attached form afused 5- to 7-membered ring which may be interrupted with one or twoheteroatoms selected from oxygen, nitrogen and sulfur wherein

-   -   R₆ is hydrogen, optionally substituted alkyl, aralkyl,        heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl,        sulfonyl or acyl provided that L₁ and R₂ are attached to carbon        atoms adjacent to each other;

L₂ is —(CHR₇)_(n)— wherein

-   -   R₇ is hydrogen, hydroxy, alkoxy, carboxy, optionally substituted        alkyl, cycloalkyl, aryl or heteroaryl;    -   n is zero or an integer from 1 to 4;

Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein

-   -   R₈ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl        or heterocyclyl;    -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl, heteroaralkyl, alkoxycarbonyl,        aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, sulfonyl,        acyl or acylamino;    -   m and r are independently zero or an integer of 1 or 2;

Q₁ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl provided that

-   -   (i) Q₁ is not 2-phenyloxazol-4-yl when    -   R₁ and R₂ are hydrogen;    -   X and Y each are CH;    -   L₁ is a single bond located at the 4-position;    -   L₂ is —(CHR₇)_(n)— wherein n is zero;    -   L₃ is —(CHR)_(s)— wherein s is zero;    -   Z is —(CH₂)_(m)O(CHR₈)_(r)— wherein R₈ is hydrogen, m is zero        and r is 2; and    -   Q₂ is oxygen; or    -   (ii) Q₁ is not hydrogen when    -   R₁ and R₂ are hydrogen;    -   X and Y each are CH;    -   L₁ is a single bond;    -   L₂ is —(CHR₇)_(n)— wherein n is zero;    -   L₃ is —(CHR)_(r)— wherein R is hydrogen and s is 1;    -   Z is —(CHR₈)_(m)— wherein m is zero; and    -   Q₂ is oxygen; or

Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ whereinR_(4a) and R_(5a) are as defined for R₄ and R₅; R₁₀ is optionallysubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; or

Q₁ is a radical of the formula

wherein

-   -   W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   W₁ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₁ is —C(O)—, —S(O)₂— or —(CH₂)_(r) — in which r is as defined        for Z;    -   V₁ is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted        alkyl or cycloalkyl; or    -   V₁ is —NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined        for R₄ and R₅ provided that        -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;            and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₂ is —(CH₂)_(p)— in which p is zero or 1;    -   V₂ is —NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b),        —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) in which    -   R_(4b) and R_(4c) are as defined for R_(4a) and R_(5b) has a        meaning as defined for R₅ provided that        -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;            and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₃ is —(CH₂)_(p)— in which p is zero or 1;    -   V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for        R₄; R₁₂ is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl,        optionally substituted alkyl, alkoxy or cycloalkyl; or        -   R₁₂ is —NR_(4c)R_(5b), in which R_(4c) and R_(5b) are as            defined for R₄ and R₅ provided that        -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;            and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero;

L₃ is —(CHR)_(s)— wherein

-   -   R is hydrogen, carboxy, optionally substituted alkyl,        cycloalkyl, aryl or heteroaryl;    -   s is zero or an integer from 1 to 3;

Q₂ is oxygen, sulfur or NR₁₃ wherein

-   -   R₁₃ is hydrogen, hydroxy or lower alkyl;

X and Y are independently CH or nitrogen; or

-   -   —X═Y— is sulfur, oxygen or —NR₁₄— wherein    -   R₁₄ is hydrogen, optionally substituted alkyl, alkoxycarbonyl,        acyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl or        sulfonyl;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

The compounds of the present invention are inhibitors of proteintyrosine phosphatases (PTPases), in particular, the compounds of formulaI inhibit PTPase-1B (PTP-1B) and T-cell PTPase (TC PTP), and thus may beemployed for the treatment of conditions mediated by PTPase activity.The compounds of the present invention may also be employed asinhibitors of other enzymes characterized with a phosphotyrosine bindingregion such as the SH2 domain. Accordingly, the compounds of formula Imay be employed for prevention or treatment of insulin resistanceassociated with obesity, glucose intolerance, diabetes mellitus,hypertension and ischemic diseases of the large and small blood vessels.The compounds of the present invention may also be employed in thetreatment, prevention or control of a number of conditions thataccompany Type 2 diabetes, including hyperlipidemia,hypertriglyceridemia, atherosclerosis, vascular restenosis, irritablebowel syndrome, pancreatitis, adipose cell tumors and carcinomas such asliposarcoma, dyslipidemia, and other disorders where insulin resistanceis indicated. In addition, the compounds of the present invention may beemployed to treat or prevent cancer, osteoporosis, neurodegenerative andinfectious diseases, and diseases involving inflammation and the immunesystem.

Another embodiment of the present invention is the use of a compound of(I) or a pharmaceutically acceptable salt thereof; or a prodrugderivative thereof for the manufacture of a medicament for inhibitingprotein tyrosine phosphatases (PTPases), in particular, the compounds offormula I inhibit PTPase-1B (PTP-1B) and T-cell PTPase (TC PTP), andthus may be employed for the treatment of conditions mediated by PTPaseactivity, for inhibiting other enzymes characterized with aphosphotyrosine binding region such as the SH2 domain for prevention ortreatment of insulin resistance associated with obesity, glucoseintolerance, diabetes mellitus, hypertension and ischemic diseases ofthe large and small blood vessels. The compounds of the presentinvention may also be employed in the treatment, prevention or controlof a number of conditions that accompany Type 2 diabetes, includinghyperlipidemia, hypertriglyceridemia, atherosclerosis, vascularrestenosis, irritable bowel syndrome, pancreatitis, adipose cell tumorsand carcinomas such as liposarcoma, dyslipidemia, and other disorderswhere insulin resistance is indicated, in addition, the for thetreatment or prevention of cancer, osteoporosis, neurodegenerative andinfectious diseases, and diseases involving inflammation and the immunesystem.

Likewise the present invention relates to a pharmaceutical compositionfor inhibiting protein tyrosine phosphatases (PTPases), in particular,the compounds of formula I inhibit PTPase-1B (PTP-1B) and T-cell PTPase(TC PTP), and thus may be employed for the treatment of conditionsmediated by PTPase activity, for inhibiting other enzymes characterizedwith a phosphotyrosine binding region such as the SH2 domain forprevention or treatment of insulin resistance associated with obesity,glucose intolerance, diabetes mellitus, hypertension and ischemicdiseases of the large and small blood vessels. The compounds of thepresent invention may also be employed in the treatment, prevention orcontrol of a number of conditions that accompany Type 2 diabetes,including hyperlipidemia, hypertriglyceridemia, atherosclerosis,vascular restenosis, irritable bowel syndrome, pancreatitis, adiposecell tumors and carcinomas such as liposarcoma, dyslipidemia, and otherdisorders where insulin resistance is indicated, in addition, the forthe treatment or prevention of cancer, osteoporosis, neurodegenerativeand infectious diseases, and diseases involving inflammation and theimmune system.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted straight or branched chain hydrocarbon groups having 1 to 20carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstitutedalkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more of the following groups: halo,hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy,amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio,alkylthiono, sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy,alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino,heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl,pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.

The term “lower alkyl” refers to those alkyl groups as described abovehaving 1 to 7, preferably 1 to 4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast 2 carbon atoms and containing a carbon to carbon double bond atthe point of attachment. Groups having 2 to 4 carbon atoms arepreferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and containing a carbon to carbon triple bond atthe point of attachment. Groups having 2 to 4 carbon atoms arepreferred.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3 to 12 carbon atoms, eachof which may be substituted by one or more substituents such as alkyl,halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino,dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and thelike.

Exemplary monocyclic hydrocarbon groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O—.

The term “alkanoyl” refers to alkyl-C(O)—.

The term “alkanoyloxy” refers to alkyl-C(O)—O—.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

The term “alkanoylamino” refers to alkyl-C(O)—NH—.

The term “alkylthio” refers to alkyl-S—.

The term “alkylaminothiocarbonyl” refers to alkyl-NHC(S)—.

The term “trialkylsilyl” refers to (alkyl)₃Si—.

The term “trialkylsilyloxy” refers to (alkyl)₃SiO—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.

The term “carboxycarbonyl” refers to HO—C(O)C(O)—.

The term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and thelike.

The term “sulfamoyl” refers to H₂NS(O)₂—, alkyl-NHS(O)₂—,(alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—,heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—, heteroaralkyl-NHS(O)₂— and thelike.

The term “sulfonamido” refers to alkyl-S(O)₂—NH—, aryl-S(O)₂—NH—,aralkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—, heteroaralkyl-S(O)₂—NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aralkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂—N(alkyl)-, heteroaralkyl-S(O)₂—N(alkyl)- and the like.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “optionally substituted amino” refers to a primary or secondaryamino group which may optionally be substituted by a substituent such asacyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,carboxycarbonyl, carbamoyl, alkylaminothiocarbonyl,arylaminothiocarbonyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each ofwhich may optionally be substituted by one to four substituents such asalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substitutedamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl,alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido,heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkanoyl” refers to aralkyl-C(O)—.

The term “aralkylthio” refers to aralkyl-S—.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂—.

The term “arylthio” refers to aryl-S—.

The term “aroyl” refers to aryl-C(O)—.

The term “aroylamino” refers to aryl-C(O)—NH—.

The term “aryloxycarbonyl” refers to aryl-O—C(O)—.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic, or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl andthe like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, benzodiazepinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] orfuro[2,3-b]pyridinyl), dihydroisoindolyl,1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups that aresubstituted with 1, 2 or 3 substituents selected from the groupconsisting of the following:

-   -   (a) alkyl;    -   (b) hydroxy (or protected hydroxy);    -   (c) halo;    -   (d) oxo (i.e. ═O);    -   (e) optionally substituted amino, alkylamino or dialkylamino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxy;    -   (i) heterocyclooxy;    -   (j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl or sulfonamido;    -   (o) aryl;    -   (p) alkylcarbonyloxy;    -   (q) arylcarbonyloxy;    -   (r) arylthio;    -   (s) aryloxy;    -   (t) alkylthio;    -   (u) formyl;    -   (v) carbamoyl;    -   (w) aralkyl; and    -   (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,        amino, acylamino, alkylamino, dialkylamino or halo.

The term “heterocyclooxy” denotes a heterocyclic group bonded through anoxygen bridge.

The term “heteroaryl” refers to an aromatic heterocycle, for examplemonocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzofuryl, and the like, optionally substituted by e.g. lower alkyl,lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

The term “heteroaroyl” refers to heteroaryl-C(O)—.

The term “heteroaroylamino” refers to heteroaryl-C(O)NH—

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

The term “heteroaralkanoyl” refers to heteroaralkyl-C(O)—.

The term “heteroaralkanoylamino” refers to heteroaralkyl-C(O)NH—.

The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl and the like.

The term “acylamino” refers to alkanoylamino, aroylamino,heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

Pharmaceutically acceptable salts of any compound of the presentinvention refer to salts formed with bases, namely cationic salts suchas alkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium salts, such asammonium, trimethylammonium, diethylammonium, andtris(hydroxymethyl)-methyl-ammonium salts, and salts with amino acids.

Similarly acid addition salts, such as those formed with mineral acids,organic carboxylic acids and organic sulfonic acids e.g. hydrochloricacid, maleic acid and methanesulfonic acid, are possible provided abasic group, such as pyridyl, constitutes part of the structure.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary prodrugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols, wherein acyl has ameaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono ordisubstituted lower alkyl esters such as the ω-(amino, mono- or di-loweralkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, theα-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester, and the like conventionally used in the art.

The present invention provides cyclic sulfamide derivatives, preferably1,1-dioxo-1,2,5-thiadiazolidine derivatives, of formula I,pharmaceutical compositions containing them, methods for preparing suchcompounds and methods of treating conditions associated with PTPaseactivity, in particular, PTP-1B and TC PTP activity, by administrationof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutical composition thereof. The compounds of thepresent invention may also be employed in combination with ligands forother enzymes characterized with a phosphotyrosine binding region suchas the SH2 domain.

Preferred are the compounds of formula I wherein

-   -   Q₂ is oxygen;    -   X and Y each are CH; or    -   —X═Y— is sulfur;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Further preferred are the compounds of the formula

wherein

R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, alkylthio,heteroaralkyl or heteroaralkoxy provided that R₁ is located at the2-position when L₃ is —(CHR)_(s)— in which s is zero; or

R₁ is optionally substituted alkyl, aralkyl, aralkoxy or aryloxyprovided that a monocyclic aryl group which is substituted at the paraposition with a methylene or ethylene bridged nitrogen containingheterocycle does not constitute part of R₁ when

-   -   (i) R₁ is located at the 2-position and L₃ is —(CHR)_(s)— in        which s is zero; and    -   (ii) X and Y each are CH;

R₂ is hydrogen; or

R₂ is —C(O)R₃ wherein

-   -   R₃ is hydroxy or optionally substituted alkoxy; or    -   R₃ is —NR₄R₅ in which R₄ and R₅ are independently hydrogen,        optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl,        aralkyl or heteroaralkyl;

L₁ is a single bond; or

L₁ is carbon which combined together with R₂ and the carbon atoms towhich L₁ and R₂ are attached form an optionally substituted fused 5- or6-membered aromatic or heteroaromatic ring provided that L₁ and R₂ areattached to carbon atoms adjacent to each other; or

L₁ is CH or nitrogen which taken together with R₂ and the carbon atomsto which L₁ and R₂ are attached form a fused 5- to 7-membered ring whichmay be interrupted with one or two heteroatoms selected from oxygen,nitrogen and sulfur provided that L₁ and R₂ are attached to carbon atomsadjacent to each other; or

L₁ is CH, oxygen, sulfur or nitrogen and L₂ is carbon which combinedtogether with L₁, R₂ and the carbon atoms to which L₁ and R₂ areattached form an optionally substituted fused 5- or 6-membered aromaticor heteroaromatic ring provided that L₁ and R₂ are attached to carbonatoms adjacent to each other; or

L₁ is —CH₂—, oxygen, sulfur or —NR₆— and L₂ is CH which taken togetherwith L₁, R₂ and the carbon atoms to which L₁ and R₂ are attached form afused 5- to 7-membered ring which may be interrupted with one or twoheteroatoms selected from oxygen, nitrogen and sulfur wherein

-   -   R₆ is hydrogen, optionally substituted alkyl, aralkyl,        heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl,        sulfonyl or acyl provided that L₁ and R₂ are attached to carbon        atoms adjacent to each other;

L₂ is —(CHR₇)_(n)— wherein

-   -   R₇ is hydrogen;    -   n is zero or an integer of 1 or 2;

Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein

-   -   R₈ is hydrogen or optionally substituted alkyl;    -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl or acyl;    -   m and r are independently zero or an integer of 1 or 2;

Q₁ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl provided that

-   -   (i) Q₁ is not 2-phenyloxazol-4-yl when    -   R₁ and R₂ are hydrogen;    -   X and Y each are CH;    -   L₁ is a single bond located at the 4-position;    -   L₂ is —(CHR₇)_(n)— wherein n is zero;    -   L₃ is —(CHR)_(s)— wherein s is zero; and    -   Z is —(CH₂)_(m)O(CHR₈)_(r)— wherein R₈ is hydrogen, m is zero        and r is 2; or    -   (ii) Q₁ is not hydrogen when    -   R₁ and R₂ are hydrogen;    -   X and Y each are CH;    -   L₁ is a single bond;    -   L₂ is —(CHR₇)_(n)— wherein n is zero;    -   L₃ is —(CHR)_(s)—wherein R is hydrogen and s is 1; and    -   Z is —(CHR₈)_(m)— wherein m is zero; or

Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ whereinR_(4a) and R_(5a) are as defined for R₄ and R₅; R₁₀ is optionallysubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; or

Q₁ is a radical of the formula

wherein

-   -   W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   W₁ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₁ is —C(O)— or —(CH₂)_(r) in which r is as defined for Z;    -   V₁ is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted        alkyl or cycloalkyl; or    -   V₁ is —NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined        for R₄ and R₅ provided that        -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;            and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₂ is —(CH₂)_(p)— in which p is zero or 1;    -   V₂ is —NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b),        —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) in which R_(4b)        and R_(4c) are as defined for R₄, and R_(5b) has a meaning as        defined for R₅ provided that        -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;            and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as            defined for R₄ and R₅;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₃ is —(CH₂)_(p)— in which p is zero or 1;    -   V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for        R₄; R₁₂ is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl,        optionally substituted alkyl, alkoxy or cycloalkyl; or        -   R₁₂ is —NR_(4c)R_(5b), in which R_(4c) and R_(5b) are as            defined for R₄ and R₅ provided that            -   (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or                2; and            -   (ii) Z is —(CHR₈)_(m)— in which m is zero;

L₃ is —(CHR)_(s)—wherein

-   -   R is hydrogen;    -   s is zero or an integer from 1 to 3;

X and Y each are CH; or

-   -   —X═Y— is sulfur;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are the compounds of formula IA of the formula

wherein

R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, optionallysubstituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy, heteroaralkylor heteroaralkoxy;

n is zero or an integer of 1 or 2;

Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein

-   -   R₈ is hydrogen;    -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl or acyl;    -   m and r are independently zero or an integer of 1 or 2;

Q₁ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl; or

Q₁ is C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein

-   -   R_(4a) and R_(5b) are independently hydrogen, optionally        substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or        heteroaralkyl;    -   R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl or heteroaralkyl;    -   q is an integer of 1 or 2;    -   s is zero or an integer of 1 or 2;

Q₃ is O, S or —NR_(6a)— wherein

-   -   R_(6a) is hydrogen, optionally substituted alkyl, aralkyl,        heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl,        sulfonyl or acyl;    -   X and Y each are CH; or    -   —X═Y— is sulfur;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are also the compounds of formula IA of the formula

wherein

R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl, optionallysubstituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy, heteroaralkylor heteroaralkoxy;

Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, (CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein

-   -   R₈ is hydrogen;    -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl or acyl;    -   m and r are independently zero or an integer of 1 or 2;

Q₁ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl; or

Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein

-   -   R_(4a) and R_(5a) are independently hydrogen, optionally        substituted alkyl, cycloalkyl,1 aryl, heterocyclyl, aralkyl or        heteroaralkyl;    -   R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl or heteroaralkyl;    -   q is an integer of 1 or 2;

s is zero or an integer of 1 or 2;

Q₃ is O, S or —NR_(6a)— wherein

-   -   R_(6a) is hydrogen, optionally substituted alkyl, aralkyl,        heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl,        sulfonyl or acyl;

X and Y each are CH; or

—X═Y— is sulfur;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Preferred are also the compounds of formula IA wherein

R₂ is hydrogen;

L₁ is a single bond;

L₂ is —(CH₂)_(n)— in which n is zero or an integer of 1 or 2;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Further preferred are the compounds of formula IA of the formula

wherein

R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl or alkylthioprovided that R₁ is located at the 2-position when s is zero; or

R₁ is optionally substituted alkyl, aralkyl, aralkoxy or aryloxyprovided that a monocyclic aryl group which is substituted at the paraposition with a methylene or ethylene bridged nitrogen containingheterocycle does not constitute part of R₁ when

-   -   (i) R₁ is located at the 2-position and s is zero; and    -   (ii) X and Y each are CH;

n is zero or an integer of 1 or 2;

s is zero or 1;

Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein

-   -   R₈ is hydrogen;    -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heteroaryl or acyl;    -   m and r are independently zero or an integer of 1 or 2;

Q₁ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl provided that

-   -   (i) Q₁ is not 2-phenyloxazol-4-yl when    -   R₁ is hydrogen;    -   X and Y each are CH;    -   n is zero;    -   s is zero; and    -   Z is —(CH₂)_(m)O(CHR₈)_(r)— wherein R₈ is hydrogen, m is zero        and r is 2; or    -   (ii) Q₁ is not hydrogen when    -   R₁ is hydrogen;    -   X and Y each are CH;    -   n is zero;    -   s is 1;    -   Z is —(CHR₈)_(m)— wherein m is zero; or

Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein

-   -   R_(4a) and R_(5a) are independently hydrogen, optionally        substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or        heteroaralkyl;    -   R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl or heteroaralkyl;    -   q is an integer of 1 or 2; or    -   Q₁ is a radical of the formula

wherein

-   -   W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   W₁ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4b) and R_(5a) are            independently hydrogen, optionally substituted alkyl,            cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₁ is —C(O)— or —(CH₂)_(r) in which r is as defined for Z;    -   V₁ is hydroxy, alkoxy, aryl, heteroaryl, optionally substituted        alkyl or cycloalkyl; or    -   V₁ is —NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined        for R_(4a) and R_(5a) provided that        -   (i) n is an integer of 1 or 2; and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are            independently hydrogen, optionally substituted alkyl,            cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₂ is —(CH₂)_(p)— in which p is zero or 1;    -   V₂ is —NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b),        —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) in which    -   R_(4b) and R_(4c) are as defined for R_(4a), and R_(5b) has a        meaning as defined for R_(5a) provided that        -   (i) n is an integer of 1 or 2; and        -   (ii) Z is —(CHR₈)_(m)— in which m is zero; or

Q₁ is a radical of the formula

wherein

-   -   W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionally        substituted alkoxy; or        -   R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are            independently hydrogen, optionally substituted alkyl,            cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₃ is —(CH₂)_(r)— in which r is zero or 1;    -   V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for        R_(4a); R₁₂ is hydrogen, aryl, heterocyclyl, aralkyl,        heteroaralkyl, optionally substituted alkyl, alkoxy or        cycloalkyl; or        -   R₁₂ is —NR_(4c)R_(5b) in which R_(4c) is as defined for            R_(4a), and R_(5b) has a meaning as defined for R_(5a)            provided that            -   (i) n is an integer of 1 or 2; and            -   (ii) Z is —(CHR₈)_(m)— in which m is zero;

X and Y each are CH; or

—X═Y— is sulfur;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Preferred are the compounds of formula ID wherein

—X═Y— is sulfur;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Preferred are also the compounds of formula ID wherein

R₁ is bromide;

X and Y each are CH;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Preferred are also the compounds of formula ID wherein

n is zero;

s is 1;

Z is —(CH₂)_(m)— in which m is zero;

Q₁ is C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein

-   -   R_(4a) and R_(5a) are independently hydrogen, optionally        substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or        heteroaralkyl;    -   R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl or heteroaralkyl;    -   q is an integer of 1 or 2;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are also the compounds of formula ID wherein

n is an integer of 1 or 2;

Z is —(CH₂)_(m)—(CH₂)_(m)O(CH₂)_(r) or —(CH₂)_(m)S(CH₂)_(r)— wherein

-   -   m is zero;    -   r is zero or 1;

Q₁ is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl;

or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.

Preferred are also the compounds of formula ID wherein

n is an integer of 1 or 2;

Z is —(CH₂)_(m)NR₉(CH₂)_(r)— wherein

-   -   R₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,        heteroaryl or acyl;    -   m is zero;    -   r is zero or 1;

Q₁ is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or

Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein

-   -   R_(4a) and R_(5a) are independently hydrogen, optionally        substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or        heteroaralkyl;    -   R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,        heterocyclyl, aralkyl or heteroaralkyl;    -   q is an integer of 1 or 2;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are also the compounds of formula ID wherein

n is an integer of 1 or 2;

Z is —(CH₂)_(m)— wherein m is zero;

Q₁ is a radical of the formula

wherein

-   -   W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen, alkyl or aryl;    -   U₁ is —C(O)— or —(CH₂)_(r)— in which r is zero;    -   V₁ is aryl, heteroaryl, optionally substituted alkyl or        cycloalkyl;        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are also the compounds of formula ID wherein

n is 1;

Z is —(CH₂)_(m)— wherein m is zero;

Q₁ is a radical of the formula

wherein

-   -   W₂ is —C(O)R_(3a) in which R_(3a) is —NR_(4a)R_(5a), and R_(4a)        and R_(5a) are independently hydrogen, optionally substituted        alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen;    -   U₂ is —(CH₂)_(p)— in which p is zero;    -   V₂ is —NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b),        —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) in which    -   R_(4b) and R_(4c) are as defined for R_(4a), and R_(5b) has a        meaning as defined for R_(5a);        or a pharmaceutically acceptable salt thereof; or a prodrug        derivative thereof.

Preferred are also the compounds of formula ID wherein

n is 1;

Z is —(CH₂)_(m) — wherein m is zero;

Q₁ is a radical of the formula

wherein

-   -   W₃ is —C(O)R_(3a) in which R_(3a) is —NR_(4a)R_(5a), and R_(4a)        and R_(5a) are independently hydrogen, optionally substituted        alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl;    -   R₁₁ is hydrogen;    -   U₃ is —(CH₂)_(p)— in which p is zero;    -   V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for        R_(4a); R₁₂ is hydrogen, aryl, heterocyclyl, aralkyl,        heteroaralkyl, optionally substituted alkyl or alkoxy; or        -   R₁₂ is —NR_(4c)R_(5b) in which R_(4c) and R_(5b) are as            defined for R_(4a) and R_(5a);            or a pharmaceutically acceptable salt thereof; or a prodrug            derivative thereof.

Particular embodiments of the invention are the compounds of formula Iof the working examples, or a pharmaceutically acceptable salt thereof;or a prodrug derivative thereof.

The compounds of the invention depending on the nature of thesubstituents, may possess one or more asymmetric centers. The resultingdiastereoisomers, enantiomers and geometric isomers are encompassed bythe instant invention.

Compounds of formula I may be prepared e.g. by cyclizing compounds ofthe formula

wherein Pg is an appropriate N-protecting group such as 4-methoxybenzyl,2,4-dimethoxybenzyl or 2-trimethylsilylethyl, and R₁₅ is hydrogen toafford compounds of the formula

wherein Pg has a meaning as defined herein above, by treatment with acoupling agent such as diisopropyl carbodiimide (DIC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl) inthe presence a base such as triethylamine (TEA) or N-methyl-morpholine(NMM) in an organic solvent such as tetrahydrofuran (THF),N,N-dimethyl-formamide (DMF) or dichoromethane (CH₂Cl₂). The reactionmay be carried out in the presence of an additive such as ofhydroxybenzotriazole (HOBt).

Compounds of formula II wherein R₁₅ is an alkyl group such as methyl,ethyl or t-butyl and the like may be obtained analogously to aliterature procedure described by Ducry, L.; Reinelt, S.; Seiler, P.;Diederich, F. Helvetica Chimica. Acta 1999, 82, 2432-47.

Compounds of formula II wherein R₁₅ is an alkyl group as defined hereinabove may be converted to compounds of formula II wherein R₁₅ ishydrogen according to methods well known in the art, e.g. compounds offormula II in which R₁₅ is methyl or ethyl can be treated with anaqueous base such as sodium or potassium hydroxide in an organic solventsuch as THF, 1,4-dioxane, methanol (MeOH) or ethanol (EtOH) to affordcompounds of formula II wherein R₁₅ is hydrogen, or compounds of formulaII in which R₁₅ is t-butyl may be treated with an acid such ashydrochloric acid (HCl) or trifluoroacetic acid (TFA) in an organicsolvent such as CH₂Cl₂ or ethyl acetate (EtOAc) to afford compounds offormula II wherein R₁₅ is hydrogen.

Compounds of formula III wherein Pg has a meaning as defined herein maythen be condensed with a variety of alcohols of the formula

wherein L₃ is —(CHR)_(s)— in which s is an integer of 1 to 3; L₁, L₂, Xand Y have meanings as defined herein; and R₁′, R₂′, Z′ and Q₁′represent R₁, R₂, Z and Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′are groups convertible to R₁, R₂, Z and Q₁, respectively, underMitsunobu conditions, e.g., in the presence of reagents such astriphenylphosphine and diethyl azodicarboxylate in an organic solventsuch as THF to form compounds of the formula

wherein L₃ is —(CHR)_(s)— in which s is an integer of 1 to 3; Pg, L₁,L₂, X and Y have meanings as defined herein; and R₁′, R₂′, Z′ and Q₁′represent R₁, R₂, Z and Q₁ as de herein; or R₁′, R₂′, Z′ and Q₁′ aregroups convertible to R₁, R₂, Z and Q₁, respectively.

Alternatively, compounds of formula V wherein L₃ is —(CHR)_(s)— in whichs is an integer of 1 to 3; Pg, L₁, L₂, X and Y have meanings as definedherein; and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as definedherein; or R₁′, R₂′, Z′ and Q₁′ are groups convertible to R₁, R₂, Z andQ₁, respectively, may be obtained by condensing a compound of formulaIII wherein Pg has a meaning as defined herein with an alkylating agentof the formula

wherein L₃ is —(CHR)_(s)— in which s is an integer of 1 to 3; Lg₁represents a leaving group, such as a halide or a sulfonate, especiallybromide, chloride, methanesulfonate or trifluoromethanesulfonate;

L₁, L₂, X and Y have meanings as defined herein; and R₁′, R₂′, Z′ andQ₁′ represent R₁, R₂, Z and Q₁ as defined herein; or R₁′, R₂′, Z′ andQ₁′ are groups convertible to R₁, R₂, Z and Q₁, in the presence of abase such as 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) in an inertsolvent such as CH₂Cl₂, THF or DMF to afford compounds of formula V.

Compounds of formula II wherein Pg has a meaning as defined herein mayalso be coupled with a variety of boronic acids of the formula

wherein L₁, L₂, X and Y have meanings as defined herein; and R₁′, R₂′,Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as defined herein; or R₁′, R₂′, Z′and Q₁′ are groups convertible to R₁, R₂, Z and Q₁, respectively, in thepresence of a copper catalyst such as copper(II) acetate and a base suchas cesium(II) carbonate (Ce₂CO₃) or TEA in an organic solvent such asTHF, 1,4-dioxane or CH₂Cl₂ to afford compounds of the formula V whereinwherein L₃ is —(CHR)_(s)— in which s is zero; Pg, L₁, L₂, X and Y havemeanings as defined herein; and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Zand Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′ are groups convertibleto R₁, R₂, Z and Q₁, respectively.

Alternatively, compounds of formula V wherein L₃ is —(CHR)_(s)— in whichs is zero; Pg, L₁, L₂, X and Y have meanings as defined herein; and R₁′,R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as defined herein; or R₁′,R₂′, Z′ and Q₁′ are groups convertible to R₁, R₂, Z and Q₁,respectively, may be obtained by reacting a compound of formula IIIwherein Pg has a meaning as defined herein with a compound of theformula

wherein Lg₂ represents a leaving group such as halide ortrifluoromethanesulfonate, preferably fluoride or chloride; L₁, L₂, Xand Y have meanings as defined herein; and R₁′, R₂′, Z′ and Q₁′represent R₁, R₂, Z and Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′are groups convertible to R₁, R₂, Z and Q₁, respectively, usingconditions well know in the art or using methods described herein ormodifications thereof, e.g., a compound of formula III may be firsttreated with a base such as Ce₂CO₃, or sodium, lithium or potassiumbis(trimethylsilyl)amide in an inert organic solvent such as THF or1,4-dioxane followed by reaction with a compound of formula VIb at atemperature ranging from room temperature (RT) to 110° C.

Compounds of formula V wherein Pg, L₁, L₂, L₃, X and Y have meanings asdefined herein; and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ asdefined herein; or R₁′, R₂′, Z′ and Q₁′ are groups convertible to R₁,R₂, Z and Q₁, respectively, may be converted to compounds of the formula

by removal of the N-protecting group according to methods well known inthe art, e.g. in particular when Pg is 4-methoxybenzyl or2,4-dimethoxybenzyl group using hydrogen in the presence of a catalystsuch as palladium on carbon in a polar organic solvent such as MeOH orEtOAc, or by treatment with an acid such as TFA in an organic solventsuch as CH₂Cl₂, preferably in the presence of an additive such ast-butyldimethylsilane or triethylsilane, or in particular when Pg is2-trimethylsilylethyl group using a fluoride reagent such astetra-n-butylammoniumfluoride in an organic solvent such as THF or1,4-dioxane.

In addition, compounds of formula I′ wherein L₁, L₂, L₃, X and Y havemeanings as defined herein; and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Zand Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′ are groups convertibleto R₁, R₂, Z and Q₁, respectively, may be prepared by condensingcompounds of the formula

wherein R₁₅ is an alkyl group as defined herein; and L₁, L₂, L₃, X, Y,R₁′, R₂′, Z′ and Q₁′ have meanings as defined for formula I′, with asulfamoyl chloride analog of the formulaCIS(O)₂NHR₁₆  (VIII)wherein R₁₆ is hydrogen or alkoxycarbonyl such as t-butoxycarbonyl or2-trimethylsilyl-ethoxycarbonyl, in the presence of a base such as TEAor NMM in an organic solvent such as acetonitrile (MeCN), CH₂Cl₂ or THFto form compounds of the formula

wherein R₁₅, R₁₆, L₁, L₂, L₃, X and Y have meanings as defined herein;and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as defined herein;or R₁′, R₂′, Z′ and Q₁′ are groups convertible to R₁, R₂, Z and Q₁,respectively.

Compounds of formula VIII wherein R₁₆ is alkoxycarbonyl may be obtainedby reacting chlorosulfonyl isocyanate with the appropriate alcohol in anorganic solvent such as MeCN, CH₂Cl₂ or THF.

Compounds of formula VII may be prepared using methods well known in theart or according to methods described herein or modifications thereof,e.g., according to the method described by Tohru Fukuyama et. al., Tet.Lett. 1997, 38 (33), 5831-34; or by reacting amines of the formula

wherein L₁, L₂, L₃, X and Y have meanings as defined herein; and R₁′,R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as defined herein; or R₁′,R₂′, Z′ and Q₁′ are groups convertible to R₁, R₂, Z and Q₁,respectively, with an acetate of the formulaLg₁-CH₂—C(O)—O—R₁₅  (XI)wherein Lg₁ and R₁₅ have meanings as defined herein, in the presence ofa base such as TEA or NMM in an inert solvent such as THF or1,4-dioxane.

Amines of formula X may be obtained according to methods well known inthe art, e.g, as described in PCT Patent Application PublicationsWO/9946236, WO/9946244, WO/9946268, WO/0119830, WO/0119831, WO/0204458and WO/0204459, or using methods described herein in the Examples, ormodifications thereof.

Compounds of formula IX wherein R₁s, L₁, L₂, L₃, X and Y have meaningsas defined herein; R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ asdefined herein; or R₁′, R₂′, Z′ and Q₁′ are groups convertible to R₁,R₂, Z and Q₁, respectively; and R₁₆ is alkoxycarbonyl, may be convertedto compounds of formula IX wherein R₁₆ is hydrogen according to methodsknown in the art, or using methods described herein, or modificationsthereof, e.g., compounds of formula IX wherein R₁₆ is t-butoxycarbonylmay be treated with an acid such as TFA, neat or in an organic solventsuch as CH₂Cl₂, or compounds of formula IX wherein R₁₆ is2-trimethylsilylethoxycarbonyl may be treated with a fluoride reagentsuch as tetra-n-butylammoniumfluoride in an organic solvent such as THFor 1,4-dioxane to afford compounds of formula IX wherein R₁₆ ishydrogen.

Alternatively, compounds of formula IX wherein R₁₅, L₁, L₂, L₃, X and Yhave meanings as defined herein; R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂,Z and Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′ are groupsconvertible to R₁, R₂, Z and Q₁, respectively; and R₁₆ is hydrogen, maybe obtained by first condensing amines of formula X with sulfamide in anaqueous solution and in the presence of a base such as sodiumbicarbonate (NaHCO₃) at an elevated temperature, preferably at theboiling point of the solution, to afford compounds of the formula

wherein L₁, L₂, L₃, X and Y have meanings as defined herein; and R₁′,R₂′, Z′ and Q₁′ represent R₁, R₂, Z and Q₁ as defined herein; or R₁′,R₂′, Z′ and Q₁′ are groups convertible to R₁, R₂, Z and Q₁,respectively. Compound of formula XII may then be converted to compoundof formula IX in which R₁₆ is hydrogen by the reaction with acetates offormula XI in the presence of a base such as sodium hydride in an inertsolvent such as THF or DMF.

Compounds of formula IX wherein R₁₅, R₁₆, L₁, L₂, L₃, X and Y havemeanings as defined herein; and R₁′, R₂′, Z′ and Q₁′ represent R₁, R₂, Zand Q₁ as defined herein; or R₁′, R₂′, Z′ and Q₁′ are groups convertibleto R₁, R₂, Z and Q₁, respectively, can be cyclized to form compounds offormula I′ using methods and conditions well known in the art, or asillustrated herein in the Examples, or modifications thereof.

In a particular embodiment of the invention, compounds of formula I maybe prepared as illustrated in Scheme I.

Compounds of formula XIII wherein R₁, R₂ and L₃ have meanings as definedherein, may be reacted with alcohols of the formula Pg-OH wherein Pg isa N-protecting group as defined herein, under Mitsunobu conditions,e.g., in the presence of triphenylphoshine and diethyl azodicarboxylateand an organic solvent such as THF, to afford compounds of formula XIV.Alternatively, compounds of formula XIII may be converted to compoundsof formula XIV by treatment with an alkylating agent of the formulaPg-Lg₁ in which Pg and Lg₁ have meanings as defined herein, in thepresence of a base such as DBU in an inert solvent such as CH₂Cl₂, THFor DMF. The subsequent reaction between compounds of formula XIV and theorganozinc reagent XV may be carried out in the presence of palladium(0)catalyst such as tris(dibenzylideneacetone)-dipalladium(0) acetate and aphosphine ligand such as tritolylphosphine in an organic solvent such asDMF to form compounds of formula XVI. Compounds of formula XVI may betreated with an acid such as TFA to remove the t-butoxycarbonylprotecting group. The resulting amines, or acid addition salts thereof,are then reacted with a N-derivatizing agent, such as an activatedderivative of a carboxylic acid, a chloroformate, an isocyanate or asulfonyl chloride, in the presence of a base such as TEA,diisopropylethylamine or NMM in an inert solvent such as MeCN, CH₂Cl₂,DMF or THF to obtain compounds of formula XVII wherein R₁₇ is—C(O)R_(5b), —C(O)OR_(5b), —C(O)NR_(4c)R_(5b) or —S(O)₂R_(5b),respectively, and R_(4a) and R_(5b) have meanings as defined herein. Thebenzyl ester may then be removed, e.g., by catalytic hydrogenation, toafford carboxylic acids of formula XVIII. Coupling of an activatedderivative of a carboxylic acid of formula XVIII with amines of theformula HNR_(4a)R_(5a) yields amides of formula XIX wherein R_(4a) andR_(5a) have meanings as defined herein. Finally, treatment with TFAaffords compounds of formula I″.

In the processes cited herein, activated derivatives of carboxylicacids, e.g., those of formula XVIII, include acid chlorides, bromidesand fluorides, mixed anhydrides, lower alkyl esters, and activatedesters thereof, and adducts formed with coupling agents such as EDCl,DIC, O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate and the like. Mixed anhydrides are preferably suchfrom pivalic acid, or lower alkyl hemiesters of carbonic acids, such asethyl or isobutyl analogs. Activated esters include, for example,succinimido, phthalimido or 4-nitrophenyl esters. The reaction of anactivated derivative of a carboxylic acid, e.g., those of formula XVIII,with an amine may be carried out in the presence of a base such as TEA,diisopropylethylamine or NMM in an inert solvent such as CH₂Cl₂, DMF orTHF. Carboxylic acids, e.g. those of formula XVIII, can be converted totheir activated derivatives using methods described herein ormodifications thereof or using methods well known in the art.

In another embodiment of the invention, compounds of formula I may beprepared as illustrated in Scheme II.

Yet in another embodiment of the invention, compounds of formula I maybe prepared as illustrated in Scheme III.

Compounds of formula XXII may be converted to compounds of formula XXIIIby the treatment with a brominating agent, e.g., dibromo isocyanuricacid, in an organic solvent such as THF or 1,4-dioxane. Compounds offormula XXIII may then be reacted with an alcohol of the formula Pg-OHwherein Pg is a suitable N-protecting group as defined herein, underMitsunobu conditions, e.g., in the presence of triphenylphoshine anddiethyl azodicarboxylate in an organic solvent such as THF to affordcompounds of formula XXIV. Alternatively, compounds of formula XXIII maybe converted to compounds of formula XXIV by treatment with analkylating agent of the formula Pg-Lg₁ in which Pg has meanings asdefined herein and Lg₁ represents a leaving group such as definedherein, in the presence of a base such as DBU in an inert solvent suchas CH₂Cl₂, THF or DMF. The subsequent reaction with carbon monoxide gas(CO) in the presence of a palladium catalyst such asbis(triphenylphoshine)palladium(II) chloride and a base such as NaHCO₃in an organic solvent such as DMF, followed by treatment with a reducingagent such as sodium borohydride, or sodium cyanoborohydride in an inertsolvent such as THF affords alcohols of formula XXV. Compounds offormula XXV may be converted to compounds of formula XXVI wherein Lg′represents a leaving group as defined herein for Lg₁, using methods wellknown in the art. Compounds of formula XXVI may be reacted with thiolsof the formula Q₁-(CH₂)_(r)—SH wherein r is, e.g., zero or 1, and Q₁ isoptionally substituted alkyl, cycloalkyl, aryl or heterocyclyl, in thepresence of base such as Ce₂CO₃ in an organic solvent such as DMF. Theresulting sulfides may then be deprotected by treatment with acid suchas TFA to afford compounds of formula I″″.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl, and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl, andhydroxyl groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxyl groups without themolecular framework being destroyed or other undesired side reactionstaking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London, New York(1973); and Greene and Wuts, “Protective Groups in Organic Synthesis”,John Wiley and Sons, Inc, New York (1999).

The above mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures (preferably ator near the boiling point of the solvents used), and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an inter-mediate product obtainable at any stage thereof is usedas starting material and the remaining steps are carried out, or inwhich the starting materials are formed in situ under the reactionconditions, or in which the reaction components are used in the form oftheir salts or optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials,intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, optical isomers (antipodes), racemates, or mixtures thereof.The aforesaid possible isomers or mixtures thereof are within thepurview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysico-chemical differences of the constituents, into the puregeometric or optical isomers, diastereoisomers, racemates, for exampleby chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g. by separationof the diastereoisomeric salts thereof, obtained with an opticallyactive acid or base, and liberating the optically active acidic or basiccompound. The carboxylic acid intermediates can thus be resolved intotheir optical antipodes e.g. by fractional crystallization of d- orl-(alpha-methylbenzylamine, cinchonidine, cinchonine, quinine,quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts.Racemic products can also be resolved by chiral chromatography, e.g.high pressure liquid chromatography using a chiral adsorbent.

Finally, compounds of the invention are either obtained in the freeform, as a salt thereof if salt forming groups are present or as prodrugderivatives thereof.

NH group of the 1,1-dioxo-1,2,5-thiadiazolidin-3-one moiety, may beconverted into salts with pharmaceutically acceptable bases. Salts maybe formed using conventional methods, advantageously in the presence ofan ethereal or alcoholic solvent, such as a lower alkanol. From thesolutions of the latter, the salts may be precipitated with ethers, e.g.diethyl ether. Resulting salts may be converted into the free compoundsby treatment with acids. These or other salts can also be used forpurification of the compounds obtained.

Compounds of the invention having basic groups can be converted intoacid addition salts, especially pharmaceutically acceptable salts.

In view of the close relationship between the free compounds, theprodrug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a prodrug derivativeand a corresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal, transdermal and parenteraladministration to mammals, including man, to inhibit protein tyrosinephosphatases, and for the treatment of conditions associated with PTPaseactivity, in particular, PTP-1B and TC PTP activity. Such conditionsinclude insulin resistance associated with obesity, glucose intolerance,diabetes mellitus, hypertension and ischemic diseases of the large andsmall blood vessels. The compounds of the present invention may also beemployed in the treatment, prevention or control of a number ofconditions that accompany Type 2 diabetes, including hyperlipidemia,hypertriglyceridemia, atherosclerosis, vascular restenosis, irritablebowel syndrome, pancreatitis, adipose cell tumors and carcinomas such asliposarcoma, dyslipidemia, and other disorders where insulin resistanceis indicated. In addition, the compounds of the present invention may beemployed to treat or prevent cancer, osteoporosis, neurodegenerative andinfectious diseases, and diseases involving inflammation and the immunesystem. The said pharmaceutical compositions comprise a therapeuticallyeffective amount of a pharmacologically active compound of the instantinvention, alone or in combination with one or more pharmaceuticallyacceptable carriers.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising atherapeutically effective amount thereof in conjunction or admixturewith excipients or carriers suitable for either enteral or parenteralapplication. Preferred are tablets and gelatin capsules comprising theactive ingredient together with a) diluents, e.g. lactose, dextrose,sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants,e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/orpolyethyleneglycol; for tablets also c) binders e.g. magnesium aluminumsilicate, starch paste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g. starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbants, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously preparedfrom fatty emulsions or suspensions. Said compositions may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50%,of the active ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

The pharmaceutical formulations contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include insulin, insulin derivatives and mimetics, insulinsecretagogues such as the sulfonylureas, e.g., Glipizide and Amaryl,insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g.,nateglinide and repaglinide, PPARα and/or PPARγ ligands, biguanides suchas metformin, aldose reductase inhibitors, alpha-glucosidase inhibitorssuch as acarbose, glycogen phosphorylase inhibitors, GLP-1, GLP-1analogs such as Exendin-4 and GLP-1 mimetics, and DPP-IV inhibitors.Thus, the methods of treatment or prevention described herein mayfurther include administering to mammals a second anti-diabetic compoundin an amount effective to treat or prevent diabetes. Similarly, themethods of treatment of diabetes may include the administration of acholesterol biosynthesis inhibitor, particularly an HMG-CoA reductaseinhibitor such as lovastatin, pitavastatin, simvastatin, pravastatin,cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin,atorvastatin, rosuvastatin and rivastatin, a squalene synthase inhibitoror FX52 and LXR ligands, cholestyramine, fibrates, nicotinic acid, andaspirin in an amount effective to improve the lipid profile. Thecombination of a cholesterol lowering agent, anti-hypertensive agent oranti-obesity agent with a PTPase inhibitor, in particular a PTP-1Binhibitor, may be beneficial in the treatment or prevention ofatherosclerosis, hypertension, obesity and other conditions that oftenare associated with Type 2 diabetes. A compound of the present inventionmay be administered either simultaneously, before or after the otheractive ingredient, either separately by the same or different route ofadministration or together in the same pharmaceutical formulation.

A unit dosage for a mammal of about 50 to 70 kg may contain betweenabout 1 mg and 1000 mg, advantageously between about 5 mg to 500 mg ofthe active ingredient. The therapeutically effective dosage of acompound of formula I is dependent on the species of warm-blooded animal(mammal), the body weight, age and individual condition, on the form ofadministration, and on the compound involved.

The compounds of the present invention are inhibitors of PTPases, inparticular PTP-1B and TC PTP, and thus may be employed for the treatmentof conditions associated with PTPase activity, in particular with PTP-1Band TC PTP activity, as described herein, e.g. insulin resistanceassociated with obesity, glucose intolerance, diabetes mellitus,hypertension and ischemic diseases of the large and small blood vessels,and conditions that accompany Type 2 diabetes, including hyperlipidemia,hypertriglyceridemia, atherosclerosis, vascular restenosis, irritablebowel syndrome, pancreatitis, adipose cell tumors and carcinomas such asliposarcoma, dyslipidemia, and other disorders where insulin resistanceis a component. In addition, the compounds of this invention may beemployed to treat or prevent cancer, osteoporosis, neurodegenerative andinfectious diseases, and diseases involving inflammation and the immunesystem.

The above-cited properties are demonstrable in vitro and in vivo tests,using advantageously mammals, e.g. mice, rats, dogs, monkeys or isolatedorgans, tissues and preparations thereof. Said compounds can be appliedin vitro in the form of solutions, e.g. preferably aqueous solutions,and in vivo either enterally, parenterally, advantageouslyintravenously, e.g. as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻³ molar and 10⁻⁹ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 1 and 500 mg/kg,preferably between about 5 and 100 mg/kg.

The activity of a compound according to the invention may be assessed bythe following methods or by following methods well described in the art(e.g. Peters G. et al. J. Biol. Chem, 2000, 275, 18201-09).

For example, the PTP-1B inhibitory activity in vitro may be determinedas follows:

Assessment of human PTP-1B (hPTP-1B) activity in the presence of variousagents is determined by measuring the amount of inorganic phosphatereleased from a phosphopeptide substrate using a 96-well microtiterplate format. The assay (100 μL) is performed in an assay buffercomprised of 50 mM TRIS (pH 7.5), 50 mM NaCl, 3 mM DTT at ambienttemperature. The assay is typically performed in the presence of 0.4%dimethyl sulfoxide (DMSO). However, concentrations as high as 10% areused with certain poorly soluble compounds. A typical reaction isinitiated by the addition of 0.4 pmoles of hPTP-1B (amino acids 1-411)to wells containing assay buffer, 3 nmoles of the syntheticphosphopeptide substrate (GNGDpYMPMSPKS), and the test compound. After10 min, 180 μL malachite green reagent (0.88 mM malachite green, 8.2 mMammonium molybdate, aqueous 1 N HCl, and 0.01% Triton X-100) is added toterminate the reaction. Inorganic phosphate, a product of the enzymereaction, is quantitiated after 15 min as the green color resulting fromcomplexing with the Malichite reagent and is determined as an A₆₂₀ usinga Molecular Devices (Sunnyvale, Calif.) SpectraMAX Plusspectrophotometer. Test compounds are solubilized in 100% DMSO (Sigma,D-8779) and diluted in DMSO. Activity is defined as the net change inabsorbance resulting from the activity of the uninhibitedhPTP-1B_([1-411]) minus that of a tube with acid-inactivatedhPTP-1B_([1-411].)

The hPTP-1B_([1-411]) is cloned by PCR from a human hippocampal cDNAlibrary (Clonetech) and inserted into a pET 19-b vector (Novagen) at theNco1 restriction site. E. coli strain BL21 (DE3) is transformed withthis clone and stored as a stock culture in 20% glycerol at −80° C. Forenzyme production, a stock culture is inoculated into Lb/Amp and grownat 37° C. Expression of PTP-1B is initiated by induction with 1 mM IPTGafter the culture had reached an OD₆₀₀=0.6. After 4 h, the bacterialpellet is collected by centrifugation. Cells are resuspended in 70 mLlysis buffer (50 mM Tris, 100 mM NaCl, 5 mM DTT, 0.1% Triton X-100,pH7.6), incubated on ice for 30 min then sonicated (4×10 sec bursts atfull power). The lysate is centrifuged at 100,000×g for 60 min and thesupernatant is buffer exchanged and purified on a cation exchange POROS20SP column followed by an anion exchange Source 30Q (Pharmacia) column,using linear NaCl gradient elutions. Enzyme is pooled, adjusted to 1mg/mL and frozen at −80° C.

Competitive binding to the active site of the enzyme can be determinedas follows:

Ligand binding is detected by acquiring ¹H-¹⁵N HSQC spectra on 250 μL of0.15 mM PTP-1B_([1-298]) in the presence and absence of added compound(1-2 mM). The binding is determined by the observation of ¹⁵N- or¹H-amide chemical shift changes in two dimensional HSQC spectra upon theaddition of a compound to ¹⁵N-label protein. Because of the ¹⁵N spectralediting, no signal from the ligand is observed, only protein signals.Thus, binding can be detected at high compound concentrations. Compoundswhich caused a pattern of chemical shift changes similar to the changesseen with known active site binders are considered positive.

All proteins are expressed in E. coli BL21 (DE3) containing plasmidsconstructed using pET19b vectors (Novagen). Uniformly ¹⁵N-labeledPTP-1B₁₋₂₉₈ is produced by growth of bacteria on minimal mediacontaining ¹⁵N-labeled ammonium chloride. All purification steps areperformed at 4° C. Cells (˜15 g) are thawed briefly at 37° C. andresuspended in 50 mL of lysis buffer containing 50 mM Tris-HCl, 150 mMNaCl, 5 mM DTT, pH 8.0 containing one tablet of Complete (EDTA-free)protease cocktail (Boehringer Mannheim), 100 μM PMSF and 100 μg/mL DNaseI. The cells are lysed by sonication. The pellet is collected at35,000×g, resuspended in 25 mL of lysis buffer using a Polytron andcollected as before. The two supernatants are combined and centrifugedfor 30 min at 100,000×g. Diafiltration using a 10 kD MWCO membrane isused to buffer exchange the protein and reduce the NaCl concentrationprior to cation exchange chromatography. Diafiltration buffer contained50 mM MES, 75 mM NaCl, 5 mM DTT, pH 6.5. Soluble supernatant is thenloaded onto a POROS 20 SP (1×10 cm) column equilibrated with cationexchange buffer (50 mM MES and 75 mM NaCl, pH 6.5) at a rate of 20mL/min. Protein is eluted from the column using a linear salt gradient(75-500 mM NaCl in 25 CV). Fractions containing PTP-1B's are identifiedand pooled according to SDS-PAGE analyses. PTP-1B₁₋₂₉₈ is furtherpurified by anion exchange chromatography using a POROS 20 HQ column(1×10 cm). The pool from cation exchange chromatography is concentratedand buffer exchanged in 50 mM Tris-HCl, pH 7.5 containing 75 mM NaCl and5 mM DTT. Protein is loaded onto column at 20 mL/min and eluted using alinear NaCl gradient (75-500 mM in 25 CV). Final purification isperformed using Sephacryl S-100 HR (Pharmacia)(50 mM HEPES, 100 mM NaCl,3 mM DTT, pH 7.5). The NMR samples are composed of uniformly ¹⁵N-labeledPTP-1B₁₋₂₉₈ (0.15 mM) and inhibitor (1-2 mM) in a 10% D₂O/90% H₂OBis-Tris-d₁₉ buffer (50 mM, pH=6.5) solution containing NaCl (50 mM),DL-1,4-Dithiothreitol-d₁₀ (5 mM) and Sodium azide (0.02%).

The ¹H-¹⁵N HSQC NMR spectra are recorded at 20° C., on Bruker DRX500 orDMX600 NMR spectrometers. In all NMR experiments, pulsed field gradientsare applied to afford the suppression of solvent signal. Quadraturedetection in the indirectly detected dimensions is accomplished by usingthe States-TPPI method. The data are processed using Bruker software andanalyzed using NMRCompass software (MSI) on Silicon Graphics computers.

The glucose and insulin lowering activity in vivo may be evaluated asfollows:

Adult male C57BL ob/ob mice (Jackson Lab, Bar Harbor, Me.) at the age of11 weeks are housed six per cage in a reversed light cycle room (lighton from 6:00 p.m. to 6:00 a.m.) and given access to Purina rodent chowand water ad libitum. On day 1 tail blood samples are taken at 8:00 amand plasma glucose levels are determined. The animals are randomlyassigned to the control and compound groups. The means of plasma glucosevalues of the groups are matched. Animals are then orally dosed withvehicle (0.5% carboxymethyl-cellulose with 0.2% Tween-80) or compounds(at 30 mg/kg) in vehicle. The mice are dosed daily for a total of 3days. On day 4 basal blood samples are taken. The plasma samples areanalyzed for glucose concentrations using a YS12700 Dual ChannelBiochemistry Analyzer (Yellow Springs Instrument Co., Yellow Springs,Ohio) and insulin concentrations using an ELISA assay.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade (° C.). If not mentioned otherwise, allevaporations are performed under reduced pressure, preferably betweenabout 15 and 100 mmHg (=20-133 mbar). The structure of final products,intermediates and starting materials is confirmed by standard analyticalmethods, e.g. microanalysis, melting point (mp) and spectroscopiccharacteristics (e.g. MS, IR, NMR). In general, abbreviations used arethose conventional in the art.

EXAMPLE 1 5-Benzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. N-Benzyl-N-sulfamidoglycine ethyl ester

A solution of N-benzylglycine ethyl ester (6.47 g, 34.5 mmol) and TEA(10.47 g, 103 mmol) in MeCN (10 mL) is treated with a solution ofsulfamoyl chloride (3.99 g, 34.5 mmol) in MeCN (20 mL) dropwise over 20min. The mixture is stirred for 3 h and filtered. The filtrate isconcentrated and the residue is partitioned between EtOAc and aqueous 3Nhydrochloric acid (HCl). The organic layer is washed with aqueous 3NHCl, saturated aqueous sodium chloride (NaCl) solution and dried overmagnesium sulfate (MgSO₄). The solvent is evaporated to affordN-benzyl-N-sulfamidoglycine ethyl ester as a yellow oil: [M−1]⁻=272.

B. 5-Benzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one

Sodium hydride (9 mg, 0.367 mmol) is added to a solution of the title Acompound, N-benzyl-N-sulfamidoglycine ethyl ester (100 mg, 0.367 mmol)in dry THF (5 mL) under N₂ atmosphere. The mixture is stirred at RT (RT)for 3 days. The mixture is acidified with 3N HCl in EtOAc. The solventsare evaporated and the residue is purified by C8 preparative reversephase LC-MS chromatography using 5%→100% MeCN in water over 13 min toafford 5-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid:[M−1]⁻=225.

(1) EXAMPLE 25-Naphthalen-1-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. N-(1-Naphthylmethyl)glycine ethyl ester

A solution of 1-aminomethylnaphthalene (2.15 g, 13.6 mmol) and TEA (1.65g, 16.3 mmol) in CH₂Cl₂ (50 mL) is treated with ethyl bromoacetate (2.28g, 13.6 mmol) dropwise over 90 min. The mixture is stirred at RT for 3 hand washed with water. The organic layer is dried over anhydrous MgSO₄and concentrated. The residue is flash chromatographed on silica gelusing CH₂Cl₂→1% MeOH in CH₂Cl₂ as the eluent to affordN-(1-naphthyl-methyl)-glycine ethyl ester as a yellow oil: [M+1]⁺=244.

B. N-(1-Naphthylmethyl)-N-sulfamidoglycine ethyl ester

A solution of the title A compound, N-(1-naphthylmethyl)glycine ethylester (870 mg, 3.58 mmol) and TEA (1.09 g, 10.7 mmol) in MeCN (10 mL) isadded dropwise over 10 min to a solution of sulfamoyl chloride (825 mg,7.15 mmol) in MeCN (10 mL). The mixture is stirred for 16 h and thesolvent is evaporated. The residue is partitioned between EtOAc andwater. The organic layer is dried over MgSO₄ and concentrated. Theresidue is flash chromatographed on silica gel using 5% MeOH in CH₂Cl₂as the eluent to afford N-(1-naphthyl-methyl)-N-sulfamidoglycine ethylester as a clear oil: [M+1]⁺=323.

C. 5-Naphthalen-1-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title B compound,N-(1-naphthylmethyl)-N-sulfamidoglycine ethyl ester (180 mg, 0.558 mmol)in 5 mL of EtOH is treated with 1N aqueous NaOH (0.67 mL) and themixture is stirred for 1 h at RT. The resulting precipitate is filtered,washed with EtOH and dried to give5-naphthalen-1-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one as thesodium salt: [M−1]⁻=275.

EXAMPLE 3

The following examples are prepared analogously to Examples 1 and 2using appropriately protected starting materials and standard reactionconditions.

Example Chemical Name MS [m/z] 3-1N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =296 acetamide 3-2[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =354 carbamic acid t-butyl ester 3-35-(4-Aminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =254 3-4 N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M− 1]⁻ = 296 acetamide 3-5[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =354 carbamic acid t-butyl ester 3-63-Phenyl-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ =386 benzyl]-propionamide

Beispiel 1 Beispiel 2 EXAMPLE 45-(3-Iodobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. N-(3-Iodobenzyl)glycine-N-sulfonic acid amide

t-Butanol (0.354 mL, 3.7 mmol) is added dropwise to a stirred solutionof chlorosulfonyl isocyanate (0.322 mL, 3.7 mmol) in 46 mL of CH₂Cl₂ at0° C. under argon atmosphere. After 1.5 h, a solution of(3-iodo-benzylamino)-acetic acid t-butyl ester (1.07 g, 3.08 mmol) andTEA (1.55 mL, 11.1 mmol) in 46 mL of CH₂Cl₂ is added. When HPLC of asmall aliquot reveals complete disappearance of the amine (less than 2h) 100 mL of 1N aqueous HCl is added to the reaction. The reactionmixture is extracted with CH₂Cl₂ (2×100 mL). The combined organic layersare dried by passing through a small column of sodium sulfate (Na₂SO₄),and evaporated to give a clear oil. This is purified by silica gelchromatography on a 35 g RediSep column with CH₂Cl₂ as the eluent. Thepure fractions are combined and concentrated to give an intermediateproduct which is dissolved in 6 mL of TFA and stirred for 2 h. The acidis removed by evaporation on a Savant SpeedVac to yieldN-(3-iodobenzyl)-glycine-N-sulfonic acid amide as a white solid:[M−1]⁻=369.

B. 5-(3-Iodobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title A compound, N-(3-iodobenzyl)glycine-N-sulfonicacid amide (459.2 mg, 1.24 mmol) in 12.4 mL of DMF is added dropwiseover a period of 10 min to a solution of diisopropyl carbodiimide (0.194mL, 1.24 mmol) in 12.4 mL of CH₂Cl₂. After an additional 1.75 h, thereaction mixture is devided into two 40 mL scintillation vials andevaporated down overnight on a Savant SpeedVac system. An attempt atpurification using a 35 g RediSep silica gel flash column with 20% EtOAcin hexane to 100% EtOAc gradient over 30 min failed, and the product isrecovered from the column by elution with 10% MeOH in CH₂Cl₂. Thismaterial is concentrated and purified via reverse phase HPLC using agradient from 10% to 90% MeCN in water over 5 min. Fractions containingthe clean product are evaporated on a Savant SpeedVac system and5-(3-iodobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one is obtained as awhite solid: mp=101-103° C.; [M−1]⁻=351.

Beispiel 1 EXAMPLE 55-(3-Nitrobenzyl)-1,1-dioxo-(1,2,5)thiadiazolidin-3-one

A. 3-Nitrobenzyl sulfamide

A solution of 3-nitrobenzylamine hydrochloride, (1.89 g, 10.0 mmol) inwater (10 mL) is treated with NaHCO₃ (840 mg, 10.0 mmol) and sulfamide,(960 mg, 10.0 mmol). The mixture is heated at reflux for 5 h. The cooledmixture is acidified to pH 2 with 1N aqueous HCl and the precipitate isfiltered, washed with water and dried under vacuum at 50° C. to afford3-nitrobenzyl sulfamide as a tan solid: [M−1]⁻=230.

B. N-(3-Nitrobenzyl)-N-sulfamidoacetic acid methyl ester

Sodium hydride (21 mg, 0.865 mmol) is added to a solution of the title Acompound, 3-nitrobenzyl sulfamide in dry DMF (5 mL) under N₂ and themixture is stirred for 20 min. Methyl bromoacetate (132 mg, 0.865 mmol)is added and the mixture is stirred at RT for 4 h. The solvent isevaporated and the residue is partitioned between EtOAc and aqueoussaturated aqueous ammonium chloride (NH₄Cl) solution. The organic layeris evaporated and the residue is flash chromatographed on silica gelusing 3% MeOH in CH₂Cl₂ as the eluent to affordN-(3-nitrobenzyl)-N-sulfamidoacetic acid methyl ester as a clear oil:[M−1]⁻=302.

(a) C. 5-(3-Nitrobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

Potassium bis(trimethylsilyl)amide (30 mg, 0.148 mmol) is added to asolution of the title B compound, N-(3-nitrobenzyl)-N-sulfamidoaceticacid methyl ester in dry THF under N₂ atmosphere. The mixture is stirredat RT for 16 h, acidified to pH 1 with 1N aqueous HCl and evaporated todryness. The residue is purified by C8 preparative reverse phase LC-MSchromatography, from 5% to 100% MeCN in water over 13 min, andfreeze-dried to afford5-(3-nitrobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid:[M−1]⁻=270.

EXAMPLE 6 5-(3-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

To a solution of the title C compound in Example 5,5-(3-nitrobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (30 mg, 0.11mmol) in EtOH (5 mL) is added palladium on carbon (10 mg) and themixture is stirred under 1 atm of hydrogen for 1 h. The catalyst isremoved by filtration through a plug of Celite which is washed withMeCN/water (1:1), (20 mL). The solvents are evaporated to afford5-(3-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a brown solid:[M−1]⁻=240.

EXAMPLE 7N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]acetamide

A solution of the title compound of Example 6,5-(3-aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.041mmol) in acetic acid (AcOH, 5 mL) is treated with acetic anhydride (85mg, 0.83 mmol) and stirred at RT for 72 h. The mixture is stirred withwater for 2 h, then concentrated to dryness. The crude mixture ispurified by LC/MS to affordN-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]acetamide:[M−1]⁻=282.

(i) EXAMPLE 8 A. Glycine-N-sulfonic acid 4-methoxybenzylamide

Glycine methyl ester-N-sulfonic acid 4-methoxybenzylamide (3.03 g, 10.5mmol, prepared analogously to literature procedure as described byDucry, L.; Reinelt, S.; Seiler, P.; Diederich, F. Helvetica Chimica.Acta. 1999, 82, 2432-47) is dissolved in 80 mL of 1,4-dioxane, thenadded 20 mL of water, followed by 21 mL of 1N aqueous NaOH solution.After 40 minutes, the 1,4-dioxane is evaporated, and the remainingaqueous solution is extracted with Et₂O. The aqueous solution isacidified with 1N aqueous HCl solution and extracted twice with EtOAc.The organic layer is dried over anhydrous Na₂SO₄, filtered andevaporated to dryness giving glycine-N-sulfonic acid4-methoxybenzylamide: [M−1]⁻=273.

(ii) B. 2-(4-Methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title A compound, glycine-N-sulfonic acid 4-methoxybenzylamide (2.51g, 9.2 mmol) is dissolved in 160 mL of THF, then HOBt (1.41 g, 9.2 mmol)is added and stirred until dissolved. EDCl (1.76 g, 9.2 mmol) is addedand stirred for 10 min, followed by the addition of TEA (1.42 mL, 10.2mmol). The reaction is stirred for 16 h, then concentrated. The residueis partitioned between 1N aqueous HCl and EtOAc. The organic layer iswashed with brine and dried over anhydrous Na₂SO₄. Filtration followedby evaporation gives an oil which solidifies on standing. This isdissolved in hot EtOAc, concentrated to 20 mL, filtered to remove solidsand chromatographed on silica gel with 40% EtOAc in hexanes to afford2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a whitesolid: mp=111-113° C.; [M−1]⁻=255.

(iii) C.2-(4-Methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one

The title B compound,2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (128 mg, 0.5mmol), 4-hydroxypyridine (109 mg, 1 mmol) and triphenylphosphine (262mg, 1 mmol) are put into a small reaction vessel under argon anddissolved in 10 mL of THF. This solution is stirred in an ice/water bathand diethyl azodicarboxylate (174 mg, 1 mmol) diluted with an equalvolume of THF is added dropwise to the stirred cold solution. Thereaction is allowed to stir 16 h while the ice bath slowly warms to RT.The solvent is evaporated on the rotary evaporator, then the residue istaken up in a minimal amount of CH₂Cl₂ and chromatographed on a 10 gRediSep silica gel column, using a gradient from 1 to 5% EtOAc in CH₂Cl₂over 15 to 20 min to afford2-(4-methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one:[M+1]⁺=348.

D. 1,1-Dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one

The title C compound,2-(4-methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one(73 mg, 0.21 mmol) in a mixture of TFA (4.75 mL) and triethylsilane(0.25 mL) in a 20 mL scintillation vial with polyseal cap is heated inan 80° C. oil bath for 16 h. The reaction solvents are removed byovernight evaporation on a Savant SpeedVac system. This gives a whitesolid which is dissolved in water, filtered through a 0.45 micron PTFEfilter disc, and water is removed by lyophilization to give1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one TFA salt as anamorphous white solid: [M+1]⁺=228.

(i) EXAMPLE 9 5-(4-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. Glycine-N-sulfonic acid 2,4-dimethoxybezylamide

Glycine methyl ester-N-sulfonic acid 2,4-dimethoxybenzylamide (14.9 g,47.0 mmol, prepared analogously to the literature procedure as describedby Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F. Helvetica Chimica.Acta. 1999, 82, 2432-47) is dissolved in 100 mL of 1,4-dioxane, then 94mL of 1N aqueous NaOH solution is added. After 120 min, the 1,4-dioxaneis evaporated on the rotary evaporator, and the remaining aqueoussolution is extracted with Et₂O. The aqueous solution is acidified with1N aqueous HCl and extracted with EtOAc. The organic layer is dried overanhydrous MgSO₄, filtered and evaporated to dryness givingglycine-N-sulfonic acid 2,4-dimethoxybenzylamide: [M−1]⁻=303.

B. 2-(2,4-Dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title A compound, glycine-N-sulfonic acid 2,4-dimethoxybenzylamide(14.3 g, 47.0 mmol) is dissolved in 300 mL of THF, then HOBt (7.20 g,47.0 mmol) is added as a solid and stirred until dissolved. EDCl (9.01g, 47.0 mmol) is added as a solid and stirred for 10 min, followed bythe addition of TEA (7.20 mL, 51.7 mmol). The reaction is stirred for 16h, then concentrated. The residue is partitioned between 1N aqueous HCland EtOAc, and the organic layer is dried over anhydrous MgSO₄.Filtration followed by evaporation gives an oil which solidifies onstanding. This is dissolved in hot EtOAc and flash chromatographed onsilica gel with 40% EtOAc in hexanes to afford2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5thiadiazolidin-3-one as a whitesolid: [M−1]⁻=285.

C.4-[5-(2,4-Dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]phenyl}-carbamicacid t-butyl ester

The title B compound,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (98 mg,0.34 mmol) and (4-hydroxymethylphenyl)carbamic acid t-butyl ester (153mg, 0.68 mmol) and triphenylphosphine (180 mg, 0.68 mmol) are dissolvedin THF (10 mL) with stirring under argon atmosphere. The reaction iscooled in an ice/water bath and diethyl azodicarboxylate (0.107 mL, 0.68mmol) dissolved in THF (0.107 mL) is added dropwise. After 16 h, thesolvent is evaporated and the residue is taken up in a minimal amount ofCH₂Cl₂ and chromatographed on silica gel with a gradient from 1 to 5%EtOAc in CH₂Cl₂ over 15 min to give{4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-carbamicacid t-butyl ester as an oil: [M+NH₄]⁺=509.

(iv) D. 5-(4-Aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

To a solution of the title C compound,{4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]phenyl}carbamicacid t-butyl ester (20 mg, 0.041 mmol) in CH₂Cl₂ (1 mL) is added TFA (1mL). The reaction is stirred at RT overnight. Upon addition the reactionbecomes light pink colored, progressing to deep purple after overnight.The solvent is evaporated and the residue is taken up in 2 mL ofMeCN/water (50/50). This is filtered through a 0.2 micron PTFE membranefilter and the filtrate is collected. MeCN is removed under reducedpressure and water via lyophilization to give5-(4-amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as ayellow foam: [M−1]⁻=240.

EXAMPLE 10

The following examples are prepared analogously to Examples 8 and 9using appropriately protected starting materials and standard reactionconditions.

Example Chemical Name MS [m/z] 10-1N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]- [M − 1]⁻ =310 butyramide 10-21-Propyl-3-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ =325 phenyl]-urea 10-34-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =283 methyl ester 10-44-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =269 10-5 2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid[M − 1]⁻ = 269 10-65-(2-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 23910-7 1,1-Dioxo-5-pyridin-3-ylmethyl-1,2,5-thiadiazolidin-3-one [M − 1]⁻= 226 10-8 1,1-Dioxo-5-pyridin-2-ylmethyl-1,2,5-thiadiazolidin-3-one [M− 1]⁻ = 226 10-95-(6-Amino-pyridin-3-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin- [M − 1]⁻= 241 3-one 10-101,1-Dioxo-5-thiophen-2-ylmethyl-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =231 10-11 5-(4-Methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 255 10-125-(4-Amino-2-bromo-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3- [M − 1]⁻ =318 one 10-13N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]- [M − 1]⁻ =282 acetamide 10-14N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]- [M − 1]⁻ =318 methanesulfonamide 10-15N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =332 methanesulfonamide 10-165-(4-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 23910-17 Amino-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-[M − 1]⁻ = 298 acetic acid 10-182-Amino-N-propyl-2-[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2- [M − 1]⁻ =339 ylmethyl)-phenyl]-acetamide 10-192-Amino-N-propyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2- [M − 1]⁻ =339 ylmethyl)-phenyl]-acetamide 10-202,2,2-Trifluoro-N-{propylcarbamoyl-[4-(1,1,4-trioxo-1,2,5- [M − 1]⁻ =435 thiadiazolidin-2-ylmethyl)-phenyl]-methyl}-acetamide 10-212-Methanesulfonylamino-N-propyl-2-[4-(1,1,4-trioxo-1,2,5- [M − 1]⁻ = 417thiadiazolidin-2-ylmethyl)-phenyl]-acetamide 10-222-Acetylamino-N-propyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin- [M + H]+= 397 2-ylmethyl)-phenyl]-propionamide 10-232-Acetylamino-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2- (mp = 197° C.)ylmethyl)-benzyl]-malonic acid diethyl ester 10-242-Amino-N-propyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2- [M − 1]⁻ =353 ylmethyl)-phenyl]-propionamide 10-252-Acetylamino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2- [M − 1]⁻ = 382ylmethyl)-phenyl]-propionic acid ethyl ester 10-26Phenyl-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-acetic acid [M − 1]⁻ =269 10-27 1,1-Dioxo-5-phenethyl-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =239 10-28 5-[2-(4-Methyl-thiazol-5-yl)-ethyl]-1,1-dioxo-1,2,5- [M − 1]⁻= 260 thiadiazolidin-3-one 10-295-[2-(3,4-Dimethoxy-phenyl)-ethyl]-1,1-dioxo-1,2,5- [M − 1]⁻ = 299thiadiazolidin-3-one 10-305-[2-(2-Chloro-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3- [M − 1]⁻= 273 one 10-315-[2-(4-Amino-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3- [M − 1]⁻= 254 one 10-322,2,2-Trifluoro-N-{4-[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)- [M −1]⁻ = 350 ethyl]-phenyl}-acetamide 10-33N-{4-[2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-ethyl]-phenyl}- [M −1]⁻ = 324 butyramide 10-341,1-Dioxo-5-(2-pyridin-3-yl-ethyl)-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =240 10-35 1,1-Dioxo-5-(2-pyridin-4-yl-ethyl)-1,2,5-thiadiazolidin-3-one[M − 1]⁻ = 240 10-363-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic [M − 1]⁻ =283 acid 10-375-[2-(3-Amino-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3- [M − 1]⁻= 254 one 10-38 5-(4-Aminomethyl-naphthalen-1-ylmethyl)-1,1-dioxo-1,2,5-[M − 1]⁻ = 304 thiadiazolidin-3-one

EXAMPLE 115-(1-Ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-one

A. 4-Ethylamino-3-nitro-benzoic acid

To a suspension of 1.85 g of 4-fluoro-3-nitrobenzoic acid (10 mmol) in25 mL of MeOH is added 20 mL of ethylamine (2.0M in THF). The resultingyellow solution is stirred at 75° C. for 5 h then at RT for 48 h. Thesolvent is removed under reduced pressure, then water is added to theresidue. The resulting orange suspension is acidified with 2N aqueousHCl and the yellow precipitate is collected by filtration, washed withwater and dried in vacuo to give 4-ethylamino-3-nitro-benzoic acid:mp=233-236° C.; ¹H-NMR (DMSO-d₆) δ 12.83 (s, 1H), 8.61 (d, J=1.84, 1H),8.49 (m, 1H), 7.97 (dd, 1H), 7.12 (d, J=9.2, 1H), 3.46 (m, 2H), 1.23 (t,3H); [M−1]⁻=209.

B. 3-Amino-4-ethylamino-benzoic acid

A solution of 1.56 g (7.4 mmol) of the title A compound4-ethylamino-3-nitro-benzoic acid in 60 mL of THF/water (2:1) ishydrogenated at 20 psi over 300 mg of Raney nickel for 18 h. Thecatalyst is removed by filtration through Celite and the solvent isremoved under reduced pressure to give 3-amino-4-ethylamino-benzoic acidas a dark solid. This material is used as such in the next step.

C. 1-Ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid

A mixture of 1.4 g (7.7 mmol) of the title B compound,3-amino-4-ethylamino-benzoic acid and 15 mL (104 mmol) of triethylorthoacetate in 20 mL of EtOH is refluxed for 7 h. The reaction mixtureis allowed to cool to RT and the precipitated solid is collected byfiltration, washed with EtOH (2×), then with methyl-t-butylether (MTBE)and dried in vacuo to give1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid as a grey solid:mp>250° C.; ¹H-NMR (DMSO-d₆) δ 12.65 (s, 1H), 8.11 (s, 1H), 7.82 (dd,1H), 7.59 (d, J=8.46, 1H), 4.26 (q, 2H), 2.57 (s, 3H), 1.30 (t, 3H);[M−1]⁻=203.

D. 1-Ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester

To a suspension of 1.1 g (5.4 mmol) of the title C compound,1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid in 25 mL of MeOH isadded dropwise 0.7 g (5.9 mmol) of thionyl chloride and the resultingsolution is stirred at 700 for 6 h, then at RT for 18 h. The solvent isremoved under reduced pressure and 8% aqueous NaHCO₃ solution is addedto the residue. The mixture is extracted with EtOAc and the organicphase is dried over anhydrous Na₂SO₄. The organic solution isconcentrated until the product precipitated. The solid is collected byfiltration, washed with EtOH and MTBE to give1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester as abeige solid: mp=118-121° C.; IR (KBr) 3430, 1695 cm⁻¹; ¹H-NMR (CDCl₃) δ8.39 (s, 1H), 7.98 (dd, 1H), 7.32 (d, J=8.45, 1H), 4.19 (q, 2H), 3.94(s, 3H), 2.64 (s, 3H), 1.43 (t, 3H); [M+1]⁺=219.

E. (1-Ethyl-2-methyl-1H-benzoimidazol-5-yl)-methanol

To a solution of 450 mg (2.06 mmol) of the title D compound,1-ethyl-2-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 5mL of THF is added dropwise 2.1 mL (2.1 mmol) of lithium aluminumhydride (LAH, 1.0M in THF). The mixture is stirred at RT for 90 min,then saturated aqueous sodium sulfate solution is carefully addeddropwise until a thick precipitate formed. MTBE is added to the mixtureand the insoluble aluminum salts are removed by filtration throughCelite. The solvent is removed under reduced pressure to give(1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-methanol as an oil: ¹H-NMR(CDCl₃) δ 7.63 (s, 1H), 7.28 (m, 2H), 4.77 (s, 2H), 4.16 (q, 2H), 3.74(t, broad, 1H), 2.60 (s, 3H), 1.40 (t, 3H); [M+1]⁺=191.

F.2-(2,4-Dimethoxy-benzyl)-5-(1-ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-one

To a solution of 767 mg (2.7 mmol) of the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, 340 mg(1.8 mmol) of the title E compound,(1-ethyl-2-methyl-1H-benzoimidazol-5-yl)-methanol and 545 mg (2.7 mmol)of tri-n-butylphosphine in 20 mL of THF is added 460 mg (2.7 mmol) ofN,N,N′,N′-tetramethyl-azodicarboxamide (TMAD). The mixture is stirred atRT for 24 h, and the resulting precipitate is filtered and washed with asmall volume of THF. The filtrate is evaporated to give an oil which ischromatographed using 5% EtOH in EtOAc to afford2-(2,4-dimethoxy-benzyl)-5-(1-ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-oneas a solid: ¹H-NMR (CDCl₃) δ 7.61 (s, 1H), 7.31-7.20 (m, 3H), 6.46 (m,2H), 4.79 (s, 2H), 4.44 (s, 2H), 4.17 (q, 2H), 3.84 (s, 3H), 3.80 (s,3H), 3.73 (s, 2H), 2.61 (s, 3H), 1.41 (t, 3H); [M+1]⁺=459.

G.5-(1-Ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-one

A solution of 200 mg (0.44 mmol) of the title F compound,2-(2,4-dimethoxy-benzyl)-5-(1-ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-onein 4 mL of TFA/CH₂Cl₂ (1:1) is stirred at RT for 90 min. The solvent isremoved from the purple solution and 4 mL of MeCN/water (1:1) is added.After stirring the mixture for 30 min, the mixture is centrifuged andthe supernatant is decanted. The solvent is removed under reducedpressure and the residue is chromatographed by preparative HPLC(gradient: 10% MeCN/water→100% MeCN, each containing 0.1% TFA). Theproper fractions are combined and lyophylized to give5-(1-ethyl-2-methyl-1H-benzoimidazol-5-ylmethyl)-1,1-dioxo-1-1,2,5-thiadiazolidin-3-oneTFA salt as an amorphous solid: mp=255-265° C.; ¹H-NMR (DMSO-d₆) δ 7.91(d, J=8.29, 1H), 7.77 (s, 1H), 7.56 (d, J=8.67, 1H), 4.44 (q, 2H), 4.27(s, 2H), 3.47 (s, 2H), 2.82 (s, 3H), 1.39 (t, 3H); [M−1]⁻=307.

EXAMPLE 125-[2-Methyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-1,1-dioxo-1-1,2,5-thiadiazolidin-3-one

The title compound is prepared analogously to Example 11: mp=70-75° C.;¹H-NMR (DMSO-d₆) δ 7.91 (d, J=8.46, 1H), 7.78 (s, 1H), 7.57 (dd, 1H),4.40 (m, 2H), 4.33 (s, 2H),3.63 (s, 2H), 2.83 (s, 3H), 1.78-1.60 (m,3H), 0.98 (d, J=5.88, 6H); [M−1]⁻=349.

EXAMPLE 135-(4-Methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. 4-Chloro-7-trifluoromethylquinoline

1.0 g (4.32 mmols) of 4-chloro-7-trifluoromethylquinoline in 20 mL of80% sulfuric acid in a sealed tube is heated to 200° C. for 18 h. Thetube is cooled to RT, vented, and poured into 200 mL water, which ismade basic with sodium hydroxide to pH 3-4. The resulting solid isfiltered and washed with water, then dissolved in 100 mL 1N aqueousNaOH, filtered to remove insolubles, and extracted with EtOAc. Theaqueous solution is acidified with 1N aqueous HCl to pH 3-4, filtered,and the collected solid washed with water. The solid is dried to give4-chloro-7-trifluoromethylquinoline: ¹H-NMR (DMSO-d₆) δ 7.90 (1H, d,J=4.8), 8.22 (1H, dd, J=8.7, 1.5), 8.32 (1H, d, J=8.7), 8.63 (1H, d,J=1.5), 8.96 (1H, d, J=4.8), 13.7 (1H, br s).

B. 7-Carbomethoxy-4-methoxyquinoline

606 mg (2.92 mmol) of the title A compound, 4-chloro-7-quinolinecarboxylic acid in 50 mL MeOH is saturated with HCl gas, then heated at60° C. for 18 h. The solvent is removed on a rotary evaporator, and theresidue taken up in water, made basic with NaHCO₃, and extracted twicewith EtOAc. Combined organic fractions are dried over anhydrous MgSO₄,filtered, and the solvent is removed to afford the crude product. Thisis chromatographed on a Biotage 40M column with 98:2 EtOAc/EtOH to give7-carbomethoxy-4-methoxyquinoline: mp=147-148° C.; ¹H-NMR (CDCl₃) δ 4.00(3H, s), 4.08 (3H, s), 6.81 (1H, d, J=5.2), 8.10 (1H, dd, J=8.7, 1.5),8.26 (1H, d, J=8.7), 8.75 (1H, d, J=1.5), 8.83 (1H, d, J=5.2);[M+1]⁺=218.

C. (4-Methoxy-quinolin-7-yl)-methanol

A solution of 2 mL of 1 M LAH (2 mmol) in 25 mL THF is cooled in an icebath. 450 mg (2.07 mmol) of the title B compound,7-carbomethoxy-4-methoxyquinoline suspended in 15 mL THF is added andallowed to stir at RT for 18 h. The mixture is quenched with saturatedaqueous Na₂SO₄, filtered, and the filtrate dried over anhydrous MgSO₄,filtered, and solvent removed to give (4-methoxyquinolin-7-yl)-methanol:¹H-NMR (CDCl₃) δ 4.04 (3H, s), 4.89 (2H, s), 6.72 (1H, d, J=5.3), 7.51(1H, d, J=8.5), 8.04 (1H, s), 8.16 (1H, d, J=8.5), 8.72 (1H, d, J=5.3).

D.2-(2,4-Dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

745 mg (2.60 mmol) of the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, 328 mg(1.73 mmol) of the title E compound, (4-methoxyquinoline-7-yl)-methanoland 448 mg (526 mg., 2.60 mmol) of tributylphosphine are stirred in 5 mLof THF. 448 mg (2.60 mmols) of TMAD is added and the mixture is stirredfor 18 h. A spatula tip of Raney nickel is added, the mixture is stirredfor 10 min, and then filtered through Celite. The filtrate is evaporatedto dryness and chromatographed on a Biotage 40M column with 98:2EtOAc/EtOH to afford2-(2,4-dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one:mp=128-132° C.; ¹H-NMR (CDCl₃) δ 3.79 (2H, s), 3.81 (3H, s), 3.85 (3H,s), 4.06 (3H, s), 4.51 (2H, s), 4.82 (2H, s), 6.46 (2H, m), 6.78 (1H, d,J=5.2) 7.30 (1H, m), 7.53 (1H, dd, J=8.5, 1.5), 7.96 (1H, s), 8.22 (1H,d J=8.5), 8.77 (1H, d, J=5.2); [M+1]⁺=458.

E.5-(4-Methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

210 mg (459 μmol) of the title D compound,2-(2,4-dimethoxy-benzyl)-5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneare stirred for 30 min in 4 mL of 1:1 TFA/CH₂Cl₂. The solvent is removedon a rotary evaporator and the residue triturated with 4 mL of 1:1MeCN/water. This mixture is filtered through a 0.2 micron disk and thesolvent is removed. The resulting material is purified by preparativeLC/MS, and the collected product fractions are lyophilized to give5-(4-methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one:[M−1]⁻=306.

EXAMPLE 145-(4-Isobutoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title compound is prepared analogously to Example 13: ¹H-NMR(DMSO-d₆) δ1.10 (3H, d, J=6.6), 2.27 (1H, m, J=6.6), 3.66 (2H, s), 4.34(2H, d, J=6.6), 4.46 (2H, s), 7.55 (1H, d, J=6.8), 7.86 (1H, dd, J=8.6,1.1), 8.14 (1H, s), 8.37 (1H, d, J=8.6), 9.15 (1H, d, J=6.8);[M+1]⁺=350, [M−1]⁻=348.

EXAMPLE 15N-(Butylcarbamoyl-phenyl-methyl)-N-(4-(1,1,4-trioxo-1,2,5-thiazodiazolidin-2-ylmethyl)-benzoyl)-amino-aceticacid

A. 4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid

To a suspension of the title B compound in Example 9,2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.87 g,48.4 mmol) and 4-bromomethylbenzoic acid (10.42 g, 48.4 mmol) in CH₂Cl₂(150 mL) is added DBU (14.5 mL, 96.9 mmol) at once and the mixture isstirred at RT overnight. The reaction mixture is washed two times with1N aqueous HCl, one time with brine, then dried over anhydrous MgSO₄ andconcentrated to a small volume to crystallize the product. The solid iscollected by filtration, washed with ethyl ether and dried under highvacuum to afford4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid: mp=175-177° C.; [M−1]⁻=419.

B.N-(Butylcarbamoyl-phenylmethyl)-N-(4-(1,1,4-trioxo-1,2,5-thiazodiazolidin-2-ylmethyl)-benzoyl)-amino-aceticacid

Wang resin (100-200 mesh, 1.11 mmol/g substitution, 3.41 g, 3.78 mmol)is suspended in pyridine (25 mL) and the mixture is shaken for 15 minand drained. The resin is resuspended in pyridine (30 mL), Fmoc-glycine(4.5 g, 15.1 mmol), 4-dimethylamino-pyridine (DMAP, 46 mg, 0.378 mmol)and N,N′-dicyclohexylcarbonylcarbodiimide (3.12 g, 15.1 mmol) are addedand the mixture is shaken overnight. The resin is drained and washedsuccessively with DMF (20 mL, 3 times), MeOH (20 mL, 2 times), THF (20mL, 1 time) and alternatively with CH₂Cl₂ (20 mL, 3 times) and MeOH (20mL, 2 times). The resin is dried under high vacuum overnight. The dryWang resin-Fmoc-glycine ester (140 mg, 0.106 mmol) is treated with 20%piperidine in CH₂Cl₂ (3 mL, 15 min, 2 times) and washed alternativelywith CH₂Cl₂ (3 mL, 2 times) and MeOH (3 mL, 2 times) and again withCH₂Cl₂ (3 mL, 2 times). The resin is then suspended in CH₂Cl₂—MeOH (1:1,4 mL), and the title A compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid (133 mg, 0.317 mmol), benzaldehyde (32 μl, 0.317 mmol) andbutylisonitrile (33 μl, 0.317 mmol) are added and the mixture is shakenfor 48 h. The resin is drained and is washed alternatively with CH₂Cl₂(4 mL, 2 times), MeOH (4 mL, 2 times) and again with CH₂Cl₂ (4 mL, 2times). The resin is then shaken with CH₂Cl₂-TFA (1:1, 4 mL) for 4 h anddrained into a receiving flask. The resin is washed with CH₂Cl₂-TFA(1:1, 4 mL) and drained into the same receiving flask. The solvents areevaporated to dryness under a stream of nitrogen and the residue isfurther dried under high vacuum. The residue is purified using aMicromass LC/MS system (Phenominex Luna 5μ, 60×21.2 mm C-8 column, 5 to100 gradient over 8 min, A=water/0.1% TFA, B=MeCN/0.1% TFA, 20 mL/minflow rate). The fractions containing the product are pooled andevaporated to a small volume which is subsequently lyophilized to giveN-(butylcarbamoyl-phenyl-methyl)-N-(4-(1,1,4-trioxo-1,2,5-thiazodiazolidin-2-ylmethyl)-benzoyl)-amino-aceticacid as a foam: [M−1]⁻=515.

EXAMPLE 16

The following examples are prepared analogously to Example 15 byreplacing benzaldehyde with the appropriate aldehyde as a startingmaterial.

Example Chemical Name MS [m/z] 16-1{[Butylcarbamoyl-(4-ethyl-phenyl)-methyl]-[4-(1,1,4-trioxo-1,2,5- [M −1]⁻ = 543 thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid 16-2{[Butylcarbamoyl-(3-phenoxy-phenyl)-methyl]-[4-(1,1,4-trioxo- [M − 1]⁻ =607 1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid 16-3{[Butylcarbamoyl-(4-methoxy-phenyl)-methyl]-[4-(1,1,4-trioxo- [M − 1]⁻ =545 1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid 16-4{[(2-Bromo-phenyl)-butylcarbamoyl-methyl]-[4-(1,1,4-trioxo- [M − 1]⁻ =593, 595 1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid16-5 {(Butylcarbamoyl-naphthalen-2-yl-methyl)-[4-(1,1,4-trioxo-1,2,5- [M− 1]⁻ = 565 thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid 16-6{[Butylcarbamoyl-(4-chloro-phenyl)-methyl]-[4-(1,1,4-trioxo- [M − 1]⁻ =549, 551 1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid16-7 {[(3-Benzyloxy-phenyl)-butylcarbamoyl-methyl]-[4-(1,1,4-trioxo- [M− 1]⁻ = 621 1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid16-8 {((E)-1-Butylcarbamoyl-3-phenyl-allyl)-[4-(1,1,4-trioxo-1,2,5- [M −1]⁻ = 541 thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-acetic acid 16-9N-(1-Butylcarbamoyl-3-phenyl-propyl)-N-(4-(1,1,4-trioxo-1,2,5- [M − 1]⁻= 543 thiazodiazolidin-2-ylmethyl)-benzoyl)-amino-acetic acid

EXAMPLE 17 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)benzoic acid4-methanesulfonyl-benzyl ester

A.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid

To a suspension of the title B compound in Example 9,2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one, (13.87 g,48.4 mmol) and 4-bromomethylbenzoic acid (10.42 g, 48.4 mmol) in CH₂Cl₂(150 mL), DBU (14.5 mL, 96.9 mmol) is added at once and the mixture isstirred at RT overnight. The reaction mixture is washed with 1N aqueousHCl, and brine, dried over anhydrous MgSO₄ and evaporated to a smallvolume to crystallize the product. The solid is collected by filtration,washed with ethyl ether and dried under high vacuum to afford4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid: mp=175-177° C.; [M−1]⁻=419.

B.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoylchloride

1.66 g (3.47 mmols) of the title A compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid and 2.5 mL (34 mmol) of SOCl₂ in 40 mL toluene are heated at 110°C. until only a small amount of dark solid remained undissolved. Thesolution is filtered and the solvent is removed on a rotary evaporatorand the residual dark purple solid is dried in a vacuum oven overnightto give4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoylchloride which is used as such without further purification.

C.4-[5-(2,4-Dimethoxy-benzyl-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methylsulfanyl-benzyl ester

400 mg (911 μmol) of the title B compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoylchloride, 140 μL (1.0 mmol) of TEA and 141 mg (914 μmol) of4-(methylthio)benzyl alcohol in 10 mL of CH₂Cl₂ are stirred at RT for 18h. The solvent is removed under reduced pressure and the residue ischromatographed on a Biotage 40M column with 98/2 —CH₂Cl₂/EtOAc to give4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methylsulfanyl-benzyl ester: [M+NH₄]⁺=574.

D.4-[5-(2,4-Dimethoxy-benzyl-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methanesulfonyl-benzyl ester

150 mg (270 μmol) of the title C compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methylsulfanyl-benzyl ester and 181 mg (810 μmols) of 81%m-chloroperbenzoic acid are stirred overnight in 10 mL of CH₂Cl₂. Thesolution is washed with saturated aqueous NaHCO₃, then dried, filtered,and solvent removed to afford4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methanesulfonyl-benzyl ester: [M+NH₄]⁺=606.

E. 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-methanesulfonyl-benzyl ester

90 mg (150 μmol) of the title D compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-methanesulfonyl-benzyl ester are stirred in 4 mL of1:1—TFA:CH₂Cl₂ for 50 min. The solvent is removed and the residuetriturated with 4 mL of 1:1—MeCN:H₂O. This mixture is filtered through a0.2μ disk and the solvent is removed. The resulting material is purifiedby LC/MS and afforded4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-methanesulfonyl-benzyl ester: ¹H-NMR (DMSO-d₆) δ 3.22 (3H, s), 3.71(2H, s), 4.27 (2H, s), 5.48 (2H, s), 7.54 (2H, d, J=8.1), 7.74 (2H, d,J=8.1), 7.96 (2H, d, J=8.5), 8.01 (2H, J=8.5); [M−1]⁻=437.

EXAMPLE 18

The following compounds are prepared analogously to Example 17 byreplacing 4-(methylthio)benzyl alcohol with the appropriate alcohol as astarting material.

Example Chemical Name MS [m/z] 18-14-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 393 chloro-benzyl ester 18-24-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 415 butyl-benzyl ester 18-34-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 389 hydroxymethyl-benzyl ester 18-44-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 463 phenethyl-benzyl ester 18-54-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =435 biphenyl-2-ylmethyl ester 18-64-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 424 difluoromethoxy-benzyl ester 18-74-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 459 (carboxy-difluoro-methyl)-thiophen-2-ylmethyl ester

EXAMPLE 19[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenylmethanesulfonyl]-aceticacid ethyl ester

A.5-(4-Bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title B compound in Example 9,2,4-dimethoxybenzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 6.98mmol) in CH₂Cl₂ (100 mL) is treated with DBU (1.06 g, 6.98 mmol). α,α′-Dibromo-p-xylene (9.2 g, 34.9 mmol) is added and the mixture isstirred at RT for 16 h. The mixture is filtered and the filtrate isconcentrated to 20 mL. The mixture is chromatographed on silica gelusing CH₂Cl₂ as the eluent. The residual α, α′-dibromo-p-xylene isremoved from the product by triturating with Et₂O to afford5-(4-bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a white solid: [M+H]⁺=469.

B.{4-[5-(2,4-Dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-benzylsulfanyl}-aceticacid ethyl ester

A solution of the title A compound,5-(4-bromomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(200 mg, 0.43 mmol) in DMF (8 mL) is treated with Cs₂CO₃ (278 mg, 0.85mmol) and mercaptoacetic acid ethyl ester (51 mg, 0.43 mmol) at RT.After 16 h, the mixture partitioned between EtOAc and water, and theorganic layer is washed with water, dried over anhydrous MgSO₄ andconcentrated. The residue is chromatographed on silica gel using 10%g→100% EtOAc in hexanes as the eluent to afford{4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-benzylsulfanyl}-aceticacid ethyl ester as a white solid.

C.{4-[5-(2,4-Dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-phenylmethanesulfonyl}-aceticacid ethyl ester

A solution of the title B compound,{4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-benzylsulfanyl}-aceticacid ethyl ester (55 mg, 0.11 mmol) in CH₂Cl₂ (5 mL) is treated with3-chloroperoxybenzoic acid (47 mg, 0.27 mmol). The mixture is stirred atRT for 4 h and then washed with saturated aqueous NaHCO₃ solution. Theorganic layer is dried over anhydrous MgSO₄, and the solvent isevaporated to afford{4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl-methanesulfonyl}-aceticacid ethyl ester: [M−H]=539.

D.[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenylmethanesulfonyl]-aceticacid ethyl ester

A solution of the title C compound,(4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-phenylmethanesulfonyl)-aceticacid ethyl ester (60 mg, 0.11 mmol) in CH₂Cl₂ (2 mL) is treated with TFA(2 mL). The mixture is stirred at RT for 16 h, and the volatiles areevaporated. The residue is stirred in MeCN/water (1:1, 6 mL) for 30 min.The mixture is passed through a 0.2μ Acrodisc and the solvents areevaporated. The residue is purified via LC/MS to afford[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenylmethane-sulfonyl]-aceticacid ethyl ester as a white solid: [M−H]⁻=389.

EXAMPLE 20[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)benzylsulfanyl]-aceticacid ethyl ester

The title compound is prepared by treating the title B compound inExample 19 with TFA using conditions described in Example 19:[M−1]⁻=357.

EXAMPLE 215-[4-(3-Methyl-butylsulfanylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title compound is prepared analogously to Example 19: [M−1]⁻=341.

EXAMPLE 22 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)benzoic acid2-ethyl-butyl ester

A. 4-Bromomethyl-benzoyl chloride

A solution of 4-bromomethyl-benzoic acid (8.6 g, 0.04 mol) in 7.23 mLSOCl₂ (0.1 mol) is heated to reflux for 5 h. SOCl₂ is removed, and theresidue is recrystalized from hexane to afford 4-bromomethyl-benzoylchloride as a white crystalline solid.

B. 4-Bromomethyl-benzoic Acid 2-ethyl-butyl ester

A solution of the title A compound, 4-bromomethyl-benzoyl chloride (466mg, 2 mmol) in 3 mL of CH₂Cl₂ is added dropwise to a solution of2-ethyl-1-butanol (204 mg, 2 mmol) and TEA (202 mg, 2 mmol) in 10 mL ofCH₂Cl₂ at 0˜5° C. over 30 min. The reaction is allowed to warm to RT andstirred overnight. The solvent is evaporated and the residue ispartitioned between hexane and water. The organic phase is dried overanhydrous MgSO₄ and concentrated. The residue is chromatographic onsilica gel using EtOAc/hexane (gradient 90-70) to give4-bromomethyl-benzoic acid 2-ethyl-butyl ester as a colorless oil.

C.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 2-ethyl-butyl ester

DBU (127 mg, 0.836 mmol) is added slowly to a suspension of the title Bcompound, 4-bromomethyl-benzoic acid 2-ethyl-butyl ester (250 mg, 0.836mmol) and the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg,0.836 mmol) in 10 mL of CH₂Cl₂ at RT. The resulting solution is stirredat RT overnight. The solvent is evaporated under reduced pressure andthe residue is chromatographed on silica gel with EtOAc/hexane (gradient60-40) to afford4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 2-ethyl-butyl ester as a white solid.

D. 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-ethyl-butyl ester

A solution of the title C compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 2-ethyl-butyl ester (230 mg, 0.456 mmol) and 2 mL of TFA in 6 mL ofCH₂Cl₂ is stirred at RT overnight. The solvent is evaporated and theresidue is treated with MeCN and filtered. The filtrate is concentratedand the residue is treated with Et₂O, filtered and the Et₂O isevaporated to give4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-ethyl-butyl ester as a light pink colored solid: [M−H]⁻=353.

EXAMPLE 23

The following compounds are prepared analogously to Example 22 byreplacing 2-ethyl-1-butanol with the appropriate alcohol as a startingmaterial.

Example Chemical Name MS [m/z] 23-14-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =339 cyclobutylmethyl ester 23-24-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =352 cyclopentylmethyl ester 23-34-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 353 methyl-pentyl ester 23-44-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =381 2,4,4-trimethyl-pentyl ester 23-54-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =365 cyclohexylmethyl ester 23-64-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 1,2- [M −1]⁻ = 339 dimethyl-propyl ester 23-74-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =337 cyclopentyl ester 23-84-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 339 methyl-butyl ester 23-94-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 343 methylsulfanyl-ethyl ester 23-104-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 387 carboxymethylsulfanyl-ethyl ester 23-114-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 394 nitro-furan-2-ylmethyl ester 23-124-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =360 pyridin-2-ylmethyl ester 23-134-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 389 hydroxymethyl-benzyl ester 23-144-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 437 methanesulfonyl-benzyl ester 23-15(4-{4-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M + 1]⁺ = 460benzoylamino]-butyl}-phenyl)-acetic acid 23-16(4-{3-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M + 1]⁺ = 446benzoylamino]-propyl}-phenyl)-acetic acid 23-174-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 406 dimethylaminomethyl-furan-2-ylmethyl ester

(i) (ii) EXAMPLE 24(S)-2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]-ethyl}-3-phenyl-propionamide

A Glycine-N-sulfonic acid 4-methoxybenzylamide

To a solution of glycine methyl ester-N-sulfonic acid4-methoxybenzylamide (3.03 g, 10.5 mmol, prepared analogously toliterature procedure as described by Ducry, L.; Reinelt, S.; Seiler, P.;Diederich, F. Helvetica Chimica. Acta. 1999, 82, 2432-47) in 80 mL of1,4-dioxane are added 20 mL of water and 21 mL of 1N aqueous NaOH. After40 min, the solvent is evaporated and the aqueous residue is extractedwith Et₂O. The aqueous solution is acidified with 1N aqueous HCl and theproduct is taken up in EtOAc, dried over anhydrous Na₂SO₄ andconcentrated to give glycine-N-sulfonic acid 4-methoxybenzyl-amide:[M−1]⁻=273.

(ii) B. 2-(4-Methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

To a solution of the title A compound, glycine-N-sulfonic acid4-methoxybenzyl-amide (2.51 g, 9.2 mmol) in 160 mL of THF is added HOBt(1.41 g, 9.2 mmol). After HOBt is dissolved, EDCl (1.76 g, 9.2 mmol) isadded and after 10 min, followed by TEA (1.42 mL, 10.2 mmol). Thereaction is stirred for 16 h, then concentrated and the residue ispartitioned between 1N aqueous HCl and EtOAc. The organic solution iswashed with brine, dried over anhydrous Na₂SO₄ and concentrated to givean oil which solidifies on standing. This is dissolved in hot EtOAc,concentrated down to 20 mL, filtered to remove solids andchromatographed on silica gel using 40% EtOAc in hexanes as the eluentto afford 2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as awhite solid: mp=111-113° C.; [M−1]⁻=255.

C.5-(3-Iodo-benzyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title B compound,2-(4-methoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (1.02 g, 3.98mmol), 3-iodo-benzyl alcohol (1.01 mL, 7.95 mmol) and triphenylphosphine(2.10 g, 8.0 mmol) in THF (50 mL) is cooled to 5° C. and treated with asolution of diethyl azodicarboxylate (1.26 mL, 8.0 mmol) in THF (10 mL).The reaction is allowed to warm to RT over 16 h. The reaction mixture isconcentrated to yield a yellow oil. This is chromatographed on a 110 gsilica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elutionof 0:100 (EtOAc:CH₂Cl₂) to 5:95 over 25 min. Fractions containingproduct are combined and concentrated to yield an oil, whichspontaneously crystalizes. Trituration with Et₂O yields5-(3-iodo-benzyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a white solid: mp=98-100° C.

D.(S)-2-t-Butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid benzyl ester

Onto zinc foil (99.9% Aldrich 35,602-6, 145 mg, 2.22 mmol) cut in smallpieces is added DMF (freshly distilled from CaH₂ under argon, 0.4 mL)and 1,2-dibromoethane (0.007 mL, 0.08 mmol) under argon. The mixture isheated at 50° C. for 10 min, then allowed to cool and trimethylsilylchloride (0.004 mL, 0.032 mmol) is added. The reaction is stirred for 25min and a solution of (R)-2-t-butoxycarbonyl-amino-3-iodo-propionic acidbenzyl ester (Fluka, 417 mg, 1.03 mmol) in DMF (1 mL) is added. After 1h, the mixture is decanted into a solution of the title C compound,5-(3-iodo-benzyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(378 mg, 0.80 mmol), tri-o-tolylphosphine (49 mg, 0.16 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (37 mg, 0.04 mmol) in DMF (2mL). After stirring for 1.5 h, the resulting reaction mixture is pouredonto water (100 mL) and extracted with EtOAc (2×100 mL). The combinedEtOAc layers are washed with water (1×200 mL) and brine (1×200 mL),dried over anhydrous MgSO₄, filtered and concentrated to give a yellowoil. This is chromatographed on a 35 g silica gel RediSep column (Isco,Inc.) with a 30 mL/min gradient elution of 15:85 (EtOAc:hexane) to 60:40over 20 min. Fractions containing product are combined and concentratedto yield(S)-2-t-butoxycarbonylamino-3-(3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid benzyl ester as a light brown foam: [M+1]⁺=624.

E.(S)-2-t-Butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid

The title D compound,(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid benzyl ester (127 mg, 0.20 mmol) is dissolved in EtOAc/EtOH (50:50)(56 mL) and 10% palladium on carbon (35 mg) is added and the mixture istreated with 45 psi of hydrogen on a Parr shaker apparatus. After two 90min runs, starting material is not completely consumed, so anotheraliquot of 10% palladium on carbon (35 mg) is added and after shaking at45 psi hydrogen for 30 min, the reaction is complete. The mixture isfiltered through celite, the filtrate is concentrated and dried to give(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid as a white foam: [M+1]⁺=534.

F.((S)-2-{3-[5-(4-Methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester

HOBt (28 mg, 0.179 mmol), pentyl amine (0.021 mL, 0.179 mmol) and EDCl(38 mg, 0.198 mmol) are added to a solution of the title E compound,(S)-2-t-butoxycarbonyl-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionicacid (96 mg, 0.179 mmol) in CH₂Cl₂ (4 mL) at RT. After 2H, the reactionis concentrated and the residue is taken up in EtOAc. The organicsolution is washed with 1N aqueous HCl, saturated aqueous NaHCO₃ andbrine, dried over anhydrous MgSO₄, filtered and concentrated to yieldthe product as an oil. This is chromatographed on a 10 g silica gelRediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 30:70(EtOAc:hexane) to 60:40 over 10 min. Fractions containing product arecombined and concentrated to yield((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester as a white foam: [M+1]⁺=603.

G.(S)-2-Amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide

To a solution of the title F compound,((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester (77 mg, 0.127 mmol) in CH₂Cl₂ (1 mL) is added TFA (1mL). After 30 min, the solvent is removed under stream of nitrogen. Theresidue is partitioned between EtOAc and saturated aqueous NaHCO₃. Theorganic solution is washed with brine, dried over anhydrous MgSO₄ andconcentrated to yield(S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamideas a clear oil: [M+1]⁺=503.

H.(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide

HOBt (19 mg, 0.125 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (26mg, 0.125 mmol) and EDCl (26 mg, 0.138 mmol) are added to a solution ofthe title G compound,(S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentylpropionamide(63 mg, 0.125 mmol) in CH₂Cl₂ (4 mL) at RT. After 30 min, the reactionis concentrated. The product is taken up in EtOAc, washed with 1Naqueous HCl, saturated aqueous NaHCO₃ and brine. The organic solution isdried over anhydrous MgSO₄ and concentrated to yield(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamideas a white foam: [M+1]⁺=692.

I.(S2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadlazolidin-2-ylmethyl)-phenyl]-ethyl}-3-phenyl-propionamide

The title H compound,(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide(77 mg, 0.111 mmol) is dissolved in TFA (2.2 mL) containingt-butyl-dimethylsilane (0.055 mL, 0.33 mmol) and heated at 80° C. for3.75 h. The reaction is concentrated under nitrogen stream and theresulting tan solid is taken up in 60% MeCN in water. Water (1 mL) isadded, and the mixture is filtered through a 0.1 micron Acrodisc filter.The filtrate is loaded onto a preparative reverse phase HPLC column (YMCCombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 7aliquots and eluted at 30 mL/min with a gradient of 90:10 (watercontaining 0.1% TFA: MeCN) to 10:90 over 5 min. Then held at 10:90 until7 min. Fractions containing product are combined and concentrated on aSavant Speedvac to yield the product still containing an unknownimpurity by HPLC. This is chromatographed again, using the same column,but a different elution gradient, 90:10 (0.1% TFA in water: MeCN) to40:60 over 14 min. Fractions containing product are combined andconcentrated to yield(S)-2-acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-ethyl}-3-phenyl-propionamideas a white film: [M+1]⁺=572.

EXAMPLE 25 5-(1H-Indol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A.N-(2-Trimethylsilanyl-ethoxycarbonyl-aminosulfonyl)-N-(1H-indol-5ylmethyl)-glycinemethyl ester

Chlorosulfonylisocyanate (0.082 mL, 0.95 mmol) is added to CH₂Cl₂ (6 mL)in a dry round bottomed flask under argon balloon, and cooled withstirring in an ice/salt/water bath. Trimethylsilylethanol (0.137 mL,0.96 mmol) in CH₂Cl₂ (1 mL) is added to this solution and stirred whilemaintaining the cooling for 1 h. Then a solution[(1H-Indol-5-ylmethyl)-amino]-acetic acid methyl ester (167 mg, 0.77mmol, obtained by alkylation of C-(1H-Indol-5-yl)-methylamine using themethod of Tohru Fukuyama et. al., Tett. Lett. 38 (33) pp. 5831-34, 1997)and TEA (0.41 mL, 2.9 mmol) in CH₂Cl₂ (6 mL) is added into this abovementioned stirred, cooled solution. After 1 h, the reaction is pouredinto 40 mL of 1N aqueous HCl and extracted with Et₂O. The ether layer iswashed with 1N aqueous HCl, separated, dried over anhydrous Na₂SO₄,filtered and concentrated. The resulting residue is chromatographed on a10 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradientelution of 15:85 (EtOAc:hexane) to 40:60 over 15 min. Fractionscontaining product are combined and evaporated yieldN-(2-trimethylsilanyl-ethoxycarbonyl-aminosulfonyl)-N-(1H-indol-5ylmethyl)-glycinemethyl ester as a yellow oil: ¹H-NMR (300 MHz, DMSO-d₆) δ 0.0 (s, 9H),0.9 (t, 2H), 3.55 (s, 3H), 3.9 (s, 2H), 4.05 (t, 2H), 4.5 (s, 2H), 6.4(s, 1H), 6.95 (d, 1H), 7.3 (m, 2H), 7.4 (s, 1H), 12.0 (s, 1H), 12.4 (s,1H).

B. 5-(1H-Indol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

Tetrabutylammonium fluoride trihydrate (252 mg, 0.80 mmol) and AcOH(0.057 mL, 1.0 mmol) are dissolved in tetrahydrofuran (4 mL) and this isused to dissolve the title A compound,N-(2-trimethylsilanyl-ethoxycarbonyl-aminosulfonyl)-N-(1H-indol-5ylmethyl)-glycinemethyl ester (90 mg, 0.20 mmol) in a thick-walled round bottomed flask.This is sealed and stirred in an oil bath at 80° C. for 16 h. Thereaction is allowed to cool, then diluted with 1N aqueous HCl (5 mL) andEt₂O (25 mL). The organic layer is separated and washed with water (2×5mL) and saturated aqueous NaCl (5 mL), then separated, dried overanhydrous MgSO₄, filtered and evaporated, to yield the crude product asa brown oil. This is taken up in water (4.5 mL), MeCN (0.7 mL) and DMSO(1 mL). The resulting mixture is loaded onto a preparative reverse phaseHPLC column (YMC CombiPrep Pro Cl 8, 50×20 mm I.D., particle size S-5micron, 12 nM) in 3 aliquots and eluted at 30 mL/min with a gradient of90:10 (water containing 0.1% TFA: MeCN) at 0 min to 10:90 at 5 min. Thenheld at 10:90 until 7 minutes. Fractions containing product are combinedand concentrated on a Savant Speedvac to yield5-(1H-indol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a lighttan foam: [M−1]⁻=264.

EXAMPLE 261,1-Dioxo-5-(3,4,5-trimethoxy-benzyl)-1,2,5-thiadiazolidin-3-one

The title compound is prepared analogously to Example 25 using3,4,5-trimethoxybenzylamine as the starting material: [M−1]⁻=315.

EXAMPLE 275-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1-1,2,5thiadiazolidin-2-ylmethyl]-benzaldehyde

DBU (4.36 g, 0.0286 mol) is added to a suspension of4-bromomethyl-benzaldehyde (5.70 g, 0.0286 mol) and the title B compoundin Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (8.2 g,0.0286 mol) in CH₂Cl₂ (100 mL) slowly at RT. After the addition iscompleted, the resulting solution is stirred overnight. The solvent isevaporated and the residue is chromatographed on silica gel withCH₂Cl₂/EtOAc (gradient 5˜25%) to afford4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-benzaldehydeas a white solid.

B.5-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A mixture of the title A compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1-1,2,5-thiadiazolidin-2-ylmethyl]-benzaldehyde(202 mg, 0.5 mmol), 1-benzylpiperazine (88 mg, 0.5 mmol) and sodiumtriacetoxyborohydride (672 mg, 1.56 mmol) in 10 mL CH₂Cl₂ is stirred atRT for 24 h. The mixture is washed with water and dried over anhydrousMgSO₄, filtered and the solvent is evaporated to dryness to give5-[4-(4-benzyl-piperazin-1-ylmethyl)-benzyl]-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-onewhich is used as such in the next step: [M+1]⁺=565.

C.5-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title B compound,5-[4-(4-benzyl-piperazin-1-ylmethyl)-benzyl]-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5]thiadiazolidin-3-one(250 mg, 0.44 mmol) dissolved in a mixture of TFA (3 mL) and CH₂Cl₂ (3mL) is stirred at RT overnight. The solvent is evaporated and theresidue is treated with a mixture of MeCN/water (50/50). The solid isfiltered off and the solvent is evaporated to dryness. The residue istreated with cold MeOH (2 mL) to afford a white solid which is collectedby filtration and washed with Et₂O to afford5-[4-(4-benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a white solid: [M+1]⁺=415, [M−1]⁻=413.

EXAMPLE 28

The following compounds are prepared by analogously to Example 27.

Example Chemical Name MS [m/z] 28-11,1-Dioxo-5-{4-[3-oxo-3H-benzofuran-(2Z)-ylidenemethyl]- [M − 1]⁻ = 369benzyl}-1,2,5-thiadiazolidin-3-one 28-2[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetic [M −1]⁻ = 283 acid 28-35-(4-Benzoyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 32928-4 1-Phenyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M −1]⁻ = 357 phenyl]-ethane-1,2-dione 28-55-Naphthalen-2-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =275 28-65-[4-(4-Methyl-pentanoyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin- [M −1]⁻ = 323 3-one 28-72-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-anthraquinone [M − 1]⁻= 355 28-85-[3-(2-Fluoro-phenoxy)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3- [M −1]⁻ = 335 one 28-93-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]- [M − 1]⁻= 389 ethoxy}-benzoic acid 28-101-(3-Methyl-butyl)-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M− 1]⁻ = 362 1H-quinolin-2-one

EXAMPLE 295-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2-carboxylicacid methyl-phenethyl-amide

A. 5-Methyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester

A solution of 5-Methyl-thiophene-2-carboxylic acid (23.58 g, 166 mmol)in MeCN (300 mL) is treated with EDCl (33.41 g, 174 mmol) and DMAP (2.03g, 16 mmol). The mixture is stirred for 5 min and2-(trimethylsilyl)ethanol (19.61 g, 166 mmol) is added. The mixture isstirred at RT for 16 h and the solvent is evaporated. The residue ispartitioned between EtOAc and water. The organic layer is diluted withan equal portion of hexane and dried over anhydrous MgSO₄. The solutionis passed through a plug of silica gel and the solvents are evaporatedto dryness to give 5-methyl-thiophene-2-carboxylic acid2-trimethylsilanyl-ethyl ester as a clear oil.

B. 5-Bromomethyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethylester

A solution of the title A compound, 5-methyl-thiophene-2-carboxylic acid2-trimethylsilanyl-ethyl ester (34.15 g, 141 mmol) in CCl₄ (200 mL) istreated with N-bromosuccinimide (NBS, 25.08 g, 141 mmol) and2,2′-azobisisobutyronitrile (1.0 g, 6 mmol). The mixture is irradiatedwith a 450 W mercury lamp for 3 h. An additional 2.5 g of NBS is addedand the mixture is further irradiated for 2 h. The mixture is filteredthrough Celite and a plug of silica gel. The solvent is evaporated togive 5-bromomethyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethylester as a yellow liquid.

C.5-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5]thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicAcid 2-trimethylsilanyl-ethyl ester

A solution of the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (7.00 g,24.4 mmol) and DBU (3.71 g, 24.4 mmol) in CH₂Cl₂ (200 mL) is treatedwith the title B compound, 5-bromomethyl-thiophene-2-carboxylic acid2-trimethylsilanyl-ethyl ester (8.25 g, 25.7 mmol). The mixture isstirred at RT for 3 h and the solvent is evaporated. The residue ischromatographed over silica gel using 20%-50% EtOAc in hexane as theeluent to afford5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5]thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid 2-trimethylsilanyl-ethyl ester as a yellow oil.

D.5-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2-carboxylicacid

A solution of the title C compound,5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5]thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid 2-trimethylsilanyl-ethyl ester (1.07 g, 2.03 mmol) in anhydrous THF(20 mL) is treated with a 1 M solution of tetrabutylammonium fluoride(4.4 mL, 4.46 mmol) in THF at RT for 3 h. The solvent is evaporated andthe residue is partitioned between EtOAc and water. The organic layer iswashed with 1N aqueous HCl and dried over anhydrous MgSO₄. The solventis evaporated to afford5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid as a yellow solid: [M−1]⁻=425.

E.5-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid methyl-phenethyl-amide

A solution of the title D compound,5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid (220 mg, 0.52 mmol) in toluene (10 mL) is treated with SOCl₂ (3 mL)and the mixture is heated at 80° C. for 1 h. The volatiles areevaporated and the residue is dissolved in toluene. The solvent isevaporated again and the residue is dissolved in CH₂Cl₂(10 mL). Amixture of N-methylphenethylamine (35 mg, 0.25 mmol) and triethylamine(39 mg, 38.7 mmol) in CH₂Cl₂ (1 mL) is added and the mixture is stirredfor 16 h. The solvent is evaporated and the residue is chromatographedover silica gel using 0-100% EtOAc in hexane as the eluent to afford5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid methyl-phenethyl-amide as a clear oil: [M+1]⁺=544.

F.5-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)thiophene-2-carboxylicacid methyl-phenethylamide

A solution of the title E compound,5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylicacid methyl-phenethyl-amide (70 mg, 0.13 mmol) in CH₂Cl₂ (2 mL) isstirred with TFA (2 mL) at RT for 4 h. The volatiles are evaporated andthe residue is stirred in equal volumes of MeCN/water (4 mL). Themixture is filtered through a 0.2μ Acrodisc and the solvents areevaporated to dryness. The residue is trituated from Et₂O to afford5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2-carboxylicacid methyl-phenethylamide as an off white solid: [M−1]⁻=392.

EXAMPLE 30

The following compounds are prepared analogously to Example 29.

Example Chemical Name MS [m/z] 30-15-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =384 carboxylic acid (2-thiophen-2-yl-ethyl)-amide 30-25-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =378 carboxylic acid phenethyl-amide 30-3[4-(2-{[5-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene- [M −1]⁻ = 436 2-carbonyl]-amino}-ethyl)-phenyl]-acetic acid 30-45-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =409 carboxylic acid 4-carboxy-benzyl ester 30-55-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =331 carboxylic acid isobutyl ester 30-65-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =330 carboxylic acid isobutyl-amide

EXAMPLE 312-Amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide

A.{4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamicacid t-butyl ester

A solution of the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (742 mg,2.59 mmol) and (4-hydroxymethyl-benzyl)-carbamic acid t-butyl ester (738mg, 3.11 mmol) in THF (15 mL) is treated with triphenylphosphine (1.36g, 5.18 mmol). The mixture is stirred for 10 min and diethylazodicarboxylate (902 mg, 5.18 mmol) is added dropwise over 1 min. Themixture is stirred for 72 h. The solvent is evaporated and the residueis chromatographed on silica gel using 1% MeOH/CH₂Cl₂ as the eluent toafford{4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamicacid t-butyl ester as a white solid: [M+NH₄]⁺=523.

B.5-(4-Aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-onehydrochloride

The title A compound,{4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamicacid t-butyl ester (400 mg, 0.79 mmol) is dissolved in EtOAc (20 mL)with gentle warming. The cooled solution is saturated with HCl gas andstirred for 30 min. The resulting precipitate is collected byfiltration, washed with EtOAc and dried to give5-(4-aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-onehydrochloride: [M+1]⁺=406.

C.({4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamicacid t-butyl ester

The title B compound,5-(4-aminomethyl-benzyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-onehydrochloride (89 mg, 0.20 mmol) is suspended in dry THF (10 mL) andN-Boc glycine (42 mg, 0.24 mmol) is added. EDCl (58 mg, 0.30 mmol) isadded, followed by TEA (61 mg, 0.60 mmol). The mixture is stirred at RTfor 16 h. The solvent is evaporated and the residue is chromatographedon silica gel using CH₂Cl₂→g 3% MeOH in CH₂Cl₂ as the eluent to afford({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamicacid t-butyl ester as a white solid: [M+NH₄]⁺=580.

D.2-Amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide

The title C compound,({4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzylcarbamoyl}-methyl)-carbamicacid t-butyl ester (80 mg, 0.14 mmol) is stirred in equal volumes ofCH₂Cl₂ and TFA (4 mL) for 16 h. The volatiles are evaporated and theresidue is stirred in equal volumes of MeCN/water (5 mL) for 30 min. Themixture is filtered through a 0.2μ Acrodisc and the solvents areevaporated. The solid is washed with Et₂O and dried to afford2-amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamideas a white solid: [M−1]⁻=311.

EXAMPLE 325-(5-{1-[(E)-Hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A.5-(5-Diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (13.9 g,48.5 mmol), (5-diethoxymethyl-thiophen-2-yl)-methanol (10.5 g, 48.5mmol) and triphenylphosphine (19.1 g, 72.2 mmol) are dissolved in dryTHF (300 mL) and the mixture is cooled to 0° C. Diethyl azodicarboxylate(12. g, 72.7 mmol) is added dropwise over 3 min and the mixture isstirred at RT for 16 h. The solvent is evaporated and the residue istaken up in Et₂O (100 mL). The solution is cooled to 0° C. and theprecipitate is filtered and discarded. The filtrate is concentrated todryness and the residue is chromatographed on silica gel using 0→100%EtOAc in hexane as the eluent to afford5-(5-diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas an orange oil.

B.5-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carbaldehyde

The title A compound,5-(5-diethoxymethyl-thiophen-2-ylmethyl)-2-(2,4-dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(3.91 g, 8.1 mmol) is dissolved in THF (100 mL) and 6N aqueous HCl (2.7mL) is added. The mixture is stirred for 2 h and the solvent isevaporated. The residue is partitioned between EtOAc and saturatedaqueous NaHCO₃ solution. The organic layer is dried over anhydrous MgSO₄and concentrated to dryness. The residue is triturated from Et₂O toafford5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carbaldehydeas a yellow solid.

C.2-(2,4-Dimethoxy-benzyl)-5-[5-(1-hydroxy-4-methyl-pentyl)-thiophen-2-ylmethyl]1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title B compound,5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carbaldehyde(545 mg, 1.33 mmol) in dry THF (8 mL) is added dropwise to a cold (−70°C.) solution of isopentylmagnesium bromide (2.22 mmol) in dry THF (10mL) keeping the temperature below −65° C. The mixture is stirred at −70°C. for 45 min and the reaction is quenched with saturated aqueous NH₄Clsolution. The mixture is diluted with EtOAc and the layers areseparated. The organic layer is dried over anhydrous MgSO₄ and thesolvent is evaporated. The residue is chromatographed on silica gelusing 0→100% EtOAc in hexane as the eluent to afford2-(2,4-dimethoxy-benzyl)-5-(5-(1-hydroxy-4-methyl-pentyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-onea yellow oil: [M+NH₄]⁺=500.

D.2-(2,4-Dimethoxy-benzyl)-5-[5-(4-methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title C compound,2-(2,4-dimethoxy-benzyl)-5-[5-(1-hydroxy-4-methyl-pentyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one(125 mg, 0.26 mmol) is dissolved in THF (10 mL) and 4-methylmorpholineN-oxide (152 mg, 1.3 mmol) is added. Tetrapropylammonium perruthenate(TPAP, 9 mg, 0.026 mmol) is added and the mixture is stirred at RT for 1h. The mixture is filtered through Celite and diluted with EtOAc. Thesolution is washed with 1N aqueous HCl and the organic layer is driedover anhydrous MgSO₄. The solvent is evaporated to afford2-(2,4-dimethoxy-benzyl)-5-[5-(4-methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a clear oil.

E.2-(2,4-Dimethoxy-benzyl)-5-(5-{1-[-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title D compound,2-(2,4-dimethoxy-benzyl)-5-[5-(4-methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one(50 mg, 0.10 mmol) is dissolved in EtOH (5 mL) and water (1 mL) isadded. Hydroxylamine hydrochloride (72 mg, 1.0 mmol) is added and themixture is heated at reflux for 4 h. The solvent is evaporated and theresidue is partitioned between EtOAc and water. The organic layer isdried over anhydrous MgSO₄ and concentrated to dryness to afford2-(2,4-dimethoxy-benzyl)-5-(5-(1-[-hydroxyimino]-4-methyl-pentyl)-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a clear oil: [M+1]⁺=496.

F.5-(5-{1-[(E)-Hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title E compound,2-(2,4-dimethoxy-benzyl)-5-(5-{1-[-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(40 mg, 0.08 mmol) is stirred in equal volumes of CH₂Cl₂ and TFA (4 mL)at RT for 3 h. The volatiles are evaporated and the residue is stirredin equal volumes of MeCN/water (5 mL) for 15 min. The mixture isfiltered through a 0.2, Acrodisc and the solvents are evaporated todryness. The residue is triturated from hexane/Et₂O (4:1) to afford5-(5-{1-[(E)-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a light pink solid: [M+1]⁺=346.

EXAMPLE 33 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)benzoic acid4-carboxy-benzyl ester

A.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid benzyl ester

To a solution of the title B compound in Example 9,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 7.0mmol) and 4-hydroxymethyl-benzoic acid benzyl ester (2.54 g, 10.5 mmol)in THF (50 mL) is added triphenylphosphine (3.67 g, 14 mmol) and themixture is stirred until dissolved. The reaction is cooled to 0° C. anddiethyl azodicarboxylate (2.20 mL, 14 mmol) dissolved in THF (20 mL) isadded dropwise. The reaction is stirred for 16 h, while allowing to warmto RT, then concentrated. The residue is taken up in CH₂Cl₂, andchromatographed in two portions on a 110 g silica gel RediSep column(Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:hexane)to 5:95 over 10 min. Fractions containing product are combined andconcentrated to yield4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid benzyl ester as a white solid.

B.4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid

The title A compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid benzyl ester (2.04 g, 4.0 mmol) is suspended in EtOAc/EtOH (1:1,100 mL) along with 10% palladium on carbon (300 mg) and treated withhydrogen (48 psi) for 4 h on a Parr Shaker. The reaction mixture isfiltered through celite and concentrated to give a white solid which isrecrystallized from MeOH to yield4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid: [M-1]-=419.

C. 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-t-butoxycarbonyl-benzyl ester

A solution of the title B compound,4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid (84 mg, 0.2 mmol) and 4-hydroxymethyl-benzoic acid t-butyl ester(42 mg, 0.2 mmol) in CH₂Cl₂ (3 mL) is treated with DMAP (12 mg, 0.1mmol) and the reaction is cooled to 5° C. EDCl (39 mg, 0.2 mmol) is thenadded and the reaction is stirred for 16 h. The mixture is concentratedand partioned between EtOAc and 1N aqueous HCl. The organic solution iswashed with saturated aqueous NaHCO₃ and brine, dried over anhydrousMgSO₄ and concentrated to give4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-t-butoxycarbonyl-benzyl ester as a white solid.

D. 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-carboxy-benzyl ester

The title C compound,4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-t-butoxycarbonyl-benzyl ester (119 mg, 0.19 mmol) is dissolved inCH₂Cl₂ (5 mL) and then added TFA (5 mL, 64.9 mmol). This is stirred for2 h and then concentrated under reduced pressure. The residue issuspended in MeCN:water (6:4) (12 mL), centrifuged, decanted andfiltered through a 0.1 micron Acrodisc filter. The resulting mixture isloaded onto a preparative reverse phase HPLC column (YMC CombiPrep ProC18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in 6 aliquots andeluted at 30 mL/min with a gradient of 90:10 (water containing 0.1% TFA:MeCN) at 0 min to 10:90 at 5 min. Then held at 10:90 until 7 min.Fractions containing product are combined and concentrated bylyophilization to yield4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-carboxy-benzyl ester as a white amorphous solid: [M−1]⁻=403.

EXAMPLE 34

The following compounds are prepared using appropriate startingmaterials and general methods described in Examples 31, 32 and 33.

Example Chemical Name MS [m/z] 34-11,1-Dioxo-5-(3-phenoxy-benzyl)-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 31734-2 3-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M− 1]⁻ = 314 acid 34-35-(4-Hydroxymethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻= 255 34-42-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic (mp =181–183° C.) acid methyl ester 34-55-(4-Hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 24134-6 5-Nitro-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M− 1]⁻ = 314 acid 34-75-Amino-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 284 acid 34-85-(4-Chloro-3-methoxy-5-nitro-benzyl)-1,1-dioxo-1,2,5- [M − 1]⁻ = 334thiadiazolidin-3-one 34-95-(2-Nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 27034-10 5-(3-Methyl-2-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one[M − 1]⁻ = 284 34-115-(3-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 23934-12 1,1-Dioxo-5-(3-phenyl-propyl)-1,2,5-thiadiazolidin-3-one [M − 1]⁻= 253 34-13 5-(4-Butoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M− 1]⁻ = 297 34-141,1-Dioxo-5-(2-trifluoromethyl-benzyl)-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 293 34-153-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 284 acid 34-164-[5-Amino-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ =326 phenyl]-butyric acid 34-175-(2-Methyl-3-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 284 34-185-(4-Methyl-3-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 284 34-195-(5-Methyl-2-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 284 34-20 5-(2-Amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one[M − 1]⁻ = 240 34-212-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =384 isoindole-1,3-dione 34-222-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]- [M − 1]⁻ =384 isoindole-1,3-dione 34-235,5′-[1,4-Phenylenebis(methylene)bis[1,2,5-thiadiazolidine-3- [M − 1]⁻ =373 one], 1,1-dioxide 34-24N-[2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]- [M − 1 ]⁻ =312 oxalamic acid 34-255-(3-Hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 24134-26 2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic[M − 1]⁻ = 284 acid 34-275-[5-(4-Nitro-phenyl)-furan-2-ylmethyl]-1,1-dioxo-1,2,5- [M − 1]⁻ = 336thiadiazolidin-3-one 34-285-(4-Fluoro-2-trifluoromethyl-benzyl)-1,1-dioxo-1,2,5- [M − 1]⁻ = 311thiadiazolidin-3-one 34-295-(3-Hydroxymethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻= 255 34-30 5-(3-Amino-5-hydroxymethyl-benzyl)-1,1-dioxo-1,2,5- [M − 1]⁻= 270 thiadiazolidin-3-one 34-315-(3-Amino-4-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M +H]⁺ = 256 34-325-(2-Amino-3-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M +H]⁺ = 256 34-335-(3-Amino-2-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 254 34-345-(2-Amino-5-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M +H]⁺ = 256 34-352,2,2-Trifluoro-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M− 1]⁻ = 350 benzyl]-acetamide 34-364-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-pyridine-2- [M − 1]⁻ =251 carbonitrile 34-374-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-pyridine-2- [M − 1]⁻ =298 carboxylic acid ethyl ester 34-385-(3,4-Dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =285 34-39 5-(3-Amino-5-hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-[M − 1]⁻ = 256 one 34-405-(3,5-Dimethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ =253 34-41(S)-3-Phenyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M +H]⁺ = 432 benzylamino]-propionic acid ethyl ester 34-42(S)-3-Phenyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M −1]⁻ = 430 benzylamino]-propionic acid ethyl ester 34-432-Amino-5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 298 acid methyl ester 34-442-Acetylamino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻= 340 benzoic acid methyl ester 34-455-(2-Benzyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 31534-465-(2,4-Bis-trifluoromethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3- [M− 1]⁻ = 361 one 34-471,1-Dioxo-5-(2,4,6-trifluoro-benzyl)-1,2,5-thiadiazolidin-3-one [M − 1]⁻= 279 34-48 5-(2-Bromo-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M −1]⁻ = 303 34-495,5′,-[[1,1′-biphenyl]-2,2′-diyl]bis(methylene)bis[1,2,5- [M − 1]⁻ = 449Thiadiazolidine-3-one], 1,1-dioxide 34-505-(4-Ethylaminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3- [M + H]⁺= 284 one 34-512-Acetylamino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻= 326 benzoic acid 34-522-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 312 acid ethyl ester 34-531,1-Dioxo-5-[4-(phenethylamino-methyl)-benzyl]-1,2,5- [M + H]⁺ = 360thadiazolidin-3-one 34-545-(4-Diethylaminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3- [M +H]⁺ = 312 one 34-552-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 374 acid benzyl ester 34-56N-Benzyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ =358 benzamide 34-575-(5-Dimethylaminomethyl-furan-2-ylmethyl)-1,1-dioxo-1,2,5- [M + H]⁺ =274 thiadiazolidin-3-one 34-58N-[2-(3-Trifluoromethyl-phenyl)-ethyl]-4-(1,1,4-trioxo-1,2,5- [M − 1]⁻ =440 thiadiazolidin-2-ylmethyl)-benzamide 34-59N-(3-Methyl-butyl)-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-[M + CH₄CN⁺]⁺ = 381 benzamide 34-60(S)-3-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic [M −1]⁻ = 283 acid 34-61(R)-3-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic [M −1]⁻ = 283 acid 34-624-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =359 benzyl ester 34-63[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic [M −1]⁻ = 299 acid 34-644-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =325 isobutyl ester 34-652-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 340 acid isobutyl ester 34-66[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic [M −1]⁻ = 313 acid methyl ester 34-674-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 433 carboxymethoxy-benzyl ester 34-685-(5-Aminomethyl-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5- [M − 1]⁻ = 260thiadiazolidin-3-one 34-694-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M + H]⁺ = 404benzylamino]-ethyl}-benzoic acid 34-70[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic [M −1]⁻ = 355 acid isobutyl ester 34-71[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic [M −1]⁻ = 389 acid benzyl ester 34-72N-Isobutyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ =324 benzamide 34-735-(5-Diethylaminomethyl-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5- [M + H]⁺ =318 thiadiazolidin-3-one 34-744-(2-{[5-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophen-2- [M +H]⁺ = 410 ylmethyl]-amino}-ethyl)-benzoic acid 34-753-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 328 acid methyl ester 34-763-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 342 acid ethyl ester 34-773-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic [M −1]⁻ = 370 acid isobutyl ester 34-785-(4-Ethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one [M − 1]⁻ = 26934-79 1,1-Dioxo-5-(3-trifluoromethyl-benzyl)-1,2,5-thiadiazolidin-3-one[M − 1]⁻ = 293 34-804-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 417 carboxymethyl-benzyl ester 34-814-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =373 phenethyl ester 34-824-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 388 phenylamino-ethyl ester 34-834-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-(3- [M −1]⁻ = 403 methoxy-phenyl)-ethyl ester 34-844-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 507 (1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl ester34-85 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2,2-[M − 1]⁻ = 339 dimethyl-propyl ester 34-864-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 383 methoxycarbonyl-2-methyl-propyl ester 34-874-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =381 2,2,4-trimethyl-pentyl ester 34-884-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 382 dimethylamino-2,2-dimethyl-propyl ester 34-894-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =527 (3aR,4S,5R,6aS)-5-benzoyloxy-2-oxo-hexahydro-cyclopenta[b]furan-4-ylmethyl ester 34-906-{[5-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophen-2- [M +H]⁺ = 376 ylmethyl]-amino}-hexanoic acid 34-915-{5-[(3-Methyl-butylamino)-methyl]-thiophen-2-ylmethyl}-1,1- [M + H]⁺ =332 dioxo-1,2,5-thiadiazolidin-3-one 34-924-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 418 methyl-4-nitro-benzyl ester 34-934-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 407 chloro-4-methyl-benzyl ester 34-945-[5-(Isobutylamino-methyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5- [M +H]⁺ = 318 thiadiazolidin-3-one 34-954-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 411 ethoxycarbonyl-pentyl ester 34-964-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-(3- [M −1]⁻ = 407 chloro-phenyl)-ethyl ester 34-974-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-m- [M −1]⁻ = 387 tolyl-ethyl ester 34-984-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2-(3- [M −1]⁻ = 441 trifluoromethyl-phenyl)-ethyl ester 34-99(R)-3-Phenyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M −1]⁻ = 430 benzylamino]-propionic acid ethyl ester 34-1005-[4-(Benzylamino-methyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin- [M −1]⁻ = 344 3-one 34-1014-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 373 methyl-benzyl ester 34-1024-Methyl-6-{[5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻= 388 thiophen-2-ylmethyl]-amino}-hexanoic acid 34-1034-[(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)methyl]-benzoic acid [4- [M− 1]⁻ = 417 (methoxycarbonyl)phenyl]methyl ester 34-1044-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 407 cyclohexyl-2-methyl-propyl ester 34-1054-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 403 phenoxy-propyl ester 34-1064-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 427 trifluoromethyl-benzyl ester 34-1074-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 427 trifluoromethyl-benzyl ester 34-1084-[(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)methyl]-benzoic acid 2- [M− 1]⁻ = 417 (4-carboxyphenyl)ethyl ester 34-1095-[5-(3-Methyl-butyryl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5- [M − 1]⁻ =315 thiadiazolidin-3-one 34-1103-[[[4-[(1,1,4-Trioxido-1,2,5-thiadiazolidin-2-yl)methyl]benzoyl]- [M −1]⁻ = 403 oxy]methyl]benzoic acid 34-1115-[4-(Isobutylamino-methyl)-benzyl]-1,1-dioxo-1,2,5- [M − 1]⁻ = 310thiadiazolidin-3-one 34-1125-{4-[(2,2-Dimethyl-propylamino)-methyl]-benzyl}-1,1-dioxo-1,2,5- [M −1]⁻ = 324 thiadiazolidin-3-one 34-1134-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =409 naphthalen-1-ylmethyl ester 34-1144-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 404 nitro-benzyl ester 34-115(4-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M + H]⁺ = 432benzoylamino]-ethyl}-phenyl)-acetic acid 34-1165-[5-(4-Methyl-pentanoyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5- [M − 1]⁻= 329 thiadiazolidin-3-one 34-1175-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-thiophene-2- [M − 1]⁻ =275 carboxylic acid 34-1184-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 404 nitro-benzyl ester 34-1194-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 412 (carboxymethyl-amino)-2,2-dimethyl-propyl ester 34-1205-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ = 409benzoyloxymethyl]-thiophene-2-carboxylic acid 34-1215-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5- [M − 1]⁻ =413 thiadiazolidin-3-one 34-1224-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =435 biphenyl-4-ylmethyl ester 34-1234-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 416 acetylamino-benzyl ester 34-1244-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 449 benzyl-benzyl ester 34-1254-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 373 methyl-benzyl ester 34-1264-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 2- [M −1]⁻ = 418 methyl-3-nitro-benzyl ester 34-127 Glycine,N-(aminosulfonyl)-N-[[4-[[(2-phenylethyl)thio]methyl]- [M − 1]⁻ = 407phenyl]methyl]-, methyl ester 34-1284-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 417 carboxymethyl-benzyl ester 34-1294-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 418 methyl-3-nitro-benzyl ester 34-1304-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 445 fluoro-2-trifluoromethyl-benzyl ester 34-1314-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2- [M −1]⁻ = 643 ylmethyl]-benzoic acid4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)- benzyl ester 34-1324-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4- [M −1]⁻ = 493 (1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl ester 34-1334-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 418 methyl-2-nitro-benzyl ester 34-1344-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid o- [M −1]⁻ = 359 tolyl ester 34-1354-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 3- [M −1]⁻ = 426 (carboxymethyl-methyl-amino)-2,2-dimethyl-propyl ester 34-1364-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =345 phenyl ester 34-1374-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 464 isobutylcarbamoyl-thiophen-2-ylmethyl ester 34-1384-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =409 naphthalen-2-ylmethyl ester 34-139N,N-Diisobutyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M +H]⁺ = 382 benzamide 34-140{4-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]- [M + H]⁺= 397 piperazin-1-yl}-acetic acid 34-1414-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid [M − 1]⁻ =395 naphthalen-2-yl ester 34-1425-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)- [M − 1]⁻ = 465benzoyloxymethyl]-thiophene-2-carboxylic acid isobutyl ester 34-1434-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 408 carbamoyl-thiophen-2-ylmethyl ester 34-1445-[4-(4-Benzyl-piperazine-1-carbonyl)-benzyl]-1,1-dioxo-1,2,5- [M − 1]⁻= 427 thiadiazolidin-3-one 34-1454-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5-(3- [M −1]⁻ = 497 phenyl-propionyl)-thiophen-2-ylmethyl ester 34-1464-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 5- [M −1]⁻ = 498 benzylcarbamoyl-thiophen-2-ylmethyl ester

EXAMPLE 35 1,1-Dioxo-5-phenyl-1,2,5-thiadiazolidin-3-one sodium salt

A. N-sulfamoylated-N-phenylglycine ethyl ester

A solution N-phenylglycine ethyl ester (1.0 g, 5.58 mmol) and TEA (1.69g, 16.7 mmol) in MeCN, 3 mL is added dropwise to a freshly preparedsolution of sulfamoyl chloride (5.58 mmol) in MeCN (5 mL) over 20 min.The mixture is stirred at room temperature (RT) for 16 h. The solvent isevaporated and the residue is partitioned between EtOAc and water. Theorganic layer is dried over anhydrous sodium sulfate (Na₂SO₄) andevaporated. The residue is flash chromatographed on silica gel using30%→50% EtOAc in hexanes as eluent to afford theN-sulfamoylated-N-phenylglycine ethyl ester as a yellow solid:[M+1]⁺=259.

B. 1,1-Dioxo-5-phenyl-1,2,5-thiadiazolidin-3-one sodium salt

A solution of the title A compound, N-sulfamoyl-N-phenylglycine ethylester (23 mg, 0.089 mmol) in EtOH is treated with 1N aqueous sodiumhydroxide (NaOH, 0.089 mL, 0.089 mmol) and the mixture is stirred at RTfor 3 h. The mixture is evaporated to dryness to afford1,1-dioxo-5-phenyl-1,2,5-thiadiazolidin-3-one sodium salt as a whitesolid: [M−1]⁻=211.

EXAMPLE 36 5-(2,4-Diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. Glycine-N-sulfonic acid 2,4-dimethoxybenzylamide

Glycine methyl ester-N-sulfonic acid 2,4-dimethoxybenzylamide (14.9 g,47.0 mmol), is prepared analogously to the literature procedure asdescribed by Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F. HelveticaChimica. Acta. 1999, 82, 2432-47, and is dissolved in 100 mL of1,4-dioxane, then 94 mL of 1N aqueous NaOH solution is added. After 120minutes, the 1,4-dioxane is evaporated in vacuo, and the remainingaqueous solution is extracted with diethyl ether. The aqueous solutionis acidified with 1N aqueous HCl solution and extracted with EtOAc twotimes. The organic layer is dried over anhydrous magnesium sulfate(MgSO₄), filtered and evaporated to dryness giving glycine-N-sulfonicacid 2,4-dimethoxybenzylamide: [M−1]⁻=303.

B. 2-(2,4-Dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title A compound, glycine-N-sulfonic acid 2,4-dimethoxybenzylamide(14.3 g, 47.0 mmol) is dissolved in 300 mL of THF, thenhydroxybenzotriazole (HOBt, 7.20 g, 47.0 mmol) is added as a solid andstirred until dissolved. EDCl (9.01 g, 47.0 mmol) is added as a solidand stirred for 10 min, followed by the addition of TEA (7.20 mL, 51.7mmol). The reaction is stirred for 16 h, then evaporated under vacuo.The residue is partitioned between 1N aqueous HCl solution and EtOAc.The organic layer is dried over anhydrous MgSO₄ and concentrated to givean oil which solidified on standing. This is dissolved in hot EtOAc andflash chromatographed on silica gel with 40% EtOAc in hexanes to afford2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a whitesolid: [M−1]⁻=285.

C.2-(2,4-Dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title B compound,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (303 mg,1.05 mmol) in dry 1,4-dioxane (5 mL) is treated with Cs₂CO₃ (342 mg,1.05 mmol). 1-Fluoro-2,4-dinitrobenzene (197 mg, 1.05 mmol) is added andthe mixture is stirred at RT for 16 h. The solvent is evaporated and theresidue is partitioned between EtOAc and 1N aqueous HCl. The organiclayer is dried over anhydrous Na₂SO₄ and concentrated. The residue ischromatographed on silica gel using 10%→100% EtOAc in hexanes as theeluent to afford2-(2,4-dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a yellow solid: [M−1]⁻=451.

D.2-(2,4-Dimethoxybenzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A mixture of the title C compound,2-(2,4-dimethoxybenzyl)-5-(2,4-dinitrophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(200 mg, 4.42 mmol) in 20 mL of MeOH/EtOAc (3:1) and 10% palladium oncarbon (100 mg) is shaken under hydrogen atmosphere at 40 psi for 1 h.The catalyst is removed by filtration and the solvents are evaporated toafford2-(2,4-dimethoxy-benzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a brown solid: [M+1]⁺=393.

E. 5-(2,4-Diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of the title D compound,2-(2,4-dimethoxybenzyl)-5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(40 mg, 0.10 mmol) is stirred in 4 mL of TFA/CH₂Cl₂ (1:1) at RT for 16h. The volatiles are evaporated and the residue is stirred in 4 mL ofMeCN/water (1:1) for 20 min. The mixture is filtered through a 0.2 μMAcrodisc and the solvents are evaporated. The residue is triturated fromdiethylether (Et₂O) to give5-(2,4-diaminophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as abrown solid: [M+1]⁺=243.

Beispiel 2 EXAMPLE 37 3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)benzoicacid methyl ester

A.3-[5-(2,4-Dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolldin-2-yl]benzoicacid methyl ester

A solution of the title B compound in Example 36,2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (115 mg,4.02 mmol) and 3-methoxycarbonyl phenylboronic acid (145 mg, 8.04 mmol)in 1,4-dioxane (5 mL) is treated with copper(II) acetate (110 mg, 6.03mmol) and CS₂CO₃ (262 mg, 8.04 mmol). The mixture is stirred at RT for16 h and the solvent is evaporated. The residue is partitioned betweenEtOAc and 1N aqueous HCl. The organic layer is dried over anhydrousNa₂SO₄ and concentrated. The residue is flash chromatographed on silicagel using 30% EtOAc in hexanes as the eluent to give3-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]benzoicacid methyl ester as a clear oil: [M+NH₄]⁺=438.

B. 3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)benzoic acid methyl ester

A solution of the title A compound,3-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]benzoicacid methyl ester is stirred in 2 mL of TFA/CH₂Cl₂ (1:1) at RT for 16 h.The volatiles are evaporated and the residue is stirred in 4 mL ofMeCN/water (1:1) for 20 min. The mixture is filtered through a 0.2 μMAcrodisc and evaporated. The residue is triturated from Et₂O at −50° C.to give 3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)benzoic acid methylester as a pink solid: [M−1]⁻=269.

EXAMPLE 38 3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid

A solution of sodium hydroxide (105.4 mg, 2.64 mmol) in water (2.54 g)is added to a solution of the Example 37 title compound,3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid methyl ester(37.1 mg, 0.137 mmol) in MeOH (5.48 mL). This is allowed to stir 13 hand then neutralized by addition of 1N aqueous HCl (2.64 mL). Thereaction mixture is loaded onto a preparative reverse phase HPLC column(YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM)in two equal aliquots and eluted at 30 mL/min with a gradient of 100:0(water containing 0.1% TFA: MeCN) for 0 min to 2.5 min, then to 10:90 at5.5 min. Then held at 10:90 until 7 min. Fractions containing theproduct are combined and concentrated on a Savant Speedvac to yield3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid as a whitepowder: API-Ms [M−H]=255.09.

EXAMPLE 39 5-(4-Aminomethyl phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title compound is prepared analogously to Example 3: [M−1]⁻=240.

EXAMPLE 40 [2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-aceticacid methyl ester

A. (2-Nitro-phenyl)-acetic acid methyl ester

(2-Nitro-phenyl)-acetic acid (10.93 g, 60.3 mmol) is dissolved in MeOH(200 mL) and HCl gas is bubbled through the solution for 10 min. Thereaction is stirred capped for 18 h, then concentrated under reducedpressure to yield (2-nitro-phenyl)-acetic acid methyl ester as a yellowoil.

B. (2-Amino-phenyl) acetic acid methyl ester

The title A compound, (2-nitro-phenyl)-acetic acid methyl ester (5.0 g,25.6 mmol) is dissolved in MeOH (125 mL) in a Parr Bottle. It is purgedwith nitrogen, then added PtO₂ (185 mg), then placed on a Parr Shakerunder 50 to 55 psi of hydrogen with shaking for 25.5 h. The reaction isopened and filtered through celite, and concentrated to yield(2-amino-phenyl) acetic acid methyl ester as an amber oil: [M+1]⁺=166.

C. [2-(t-Butoxycarbonylmethyl-amino)-phenyl]-acetic acid methyl ester

The title B compound, (2-amino-phenyl) acetic acid methyl ester (4.2 g,25.4 mmol) is dissolved in DMF (30 mL). Powdered potassium carbonate(8.78 g, 63.5 mmol) and t-butyl bromoacetate (4.12 mL, 27.9 mmol) areadded and the reaction is stirred at room temperature for 18 h and thenat 50° C. for 1 h. The reaction is diluted with water (300 mL) andextracted with EtOAc (2×200 mL). Combined EtOAc layers are washed withwater (2×100 mL) then brine (100 mL), dried over anhydrous MgSO₄,filtered and concentrated to give a viscous brown oil. This residue ischromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 25:75 over 30 min.Fractions containing product are combined and evaporated to yield[2-(t-butoxy-carbonylmethyl-amino)-phenyl]-acetic acid methyl ester as aclear amber oil: [M+1]⁺=280.

D.N-(t-Butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonylmethyl)-phenyl]-glycinet-butyl ester

Chlorosulfonylisocyanate (1.42 mL, 16.4 mmol) is added to CH₂Cl₂ (20 mL)in a dry flask under argon balloon, and cooled with stirring in anice/salt/water bath. t-Butanol (1.57 mL, 16.4 mmol) is added to thissolution and stirred while maintaining the cooling for 1 h. Then asolution of the title C compound,[2-(t-butoxycarbonylmethyl-amino)-phenyl]-acetic acid methyl ester (3.84g, 13.7 mmol) and TEA (5.7 mL, 41.1 mmol) in CH₂Cl₂ (90 mL) is rapidlycannulated into this above mentioned stirred, cooled solution. During 18h the reaction slowly warms to RT, then concentrated and partitionedbetween EtOAc and 0.5N aqueous HCl (2×50 mL). The organic solution iswashed with brine (25 mL), dried over anhydrous MgSO₄, filtered andconcentrated. The resulting residue is chromatographed on a 110 g silicagel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of10:90 (EtOAc:hexane) to 30:70 over 30 min, maintained at 30:70 for 15min then to 50:50 over 6 min. Fractions containing product are combinedand evaporated to give an oil which on standing in a high vacuum foamedto yieldN-(t-butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonylmethyl)-phenyl]-glycinet-butyl ester as a white foam: [M−1]⁻=457.

E. N-Sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl]glycine

The title D compound,N-(t-butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonyl-methyl)-phenyl]-glycinet-butyl ester (1.87 g, 4.07 mmol) is dissolved in a mixture of TFA (35mL) and CH₂Cl₂ (35 mL) and stirred for 30 min. The reaction isconcentrated in vacuo, then triturated with diethyl ether to yieldN-sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl]glycine as a clearglass.

F. [2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acidmethyl ester

Carbonyl diimidazole (60 mg, 0.37 mmol) is added as solid to a solutionof the title E compound,N-sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl] glycine (112 mg, 0.37mmol) in THF (5 mL). After 65 h, the solvent is removed by evaporation.The residue is taken up in EtOAc and washed with 1N aqueous HCl followedby brine. The organic solution is dried over anhydrous MgSO₄, filteredand concentrated. This residue is then evaporated from diethyl ether toyield [2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acidmethyl ester as a white foam: [M−1]⁻=283.

EXAMPLE 41 [2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-aceticacid

A solution of 2N aqueous NaOH (2.0 mL, 4.0 mmol) is added to a solutionof the title compound of Example 40,[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid methylester (57 mg, 0.20 mmol) in MeOH (2.0 mL). The reaction is stirred for 3h, then neutralized by addition of 2N aqueous HCl (2.0 mL). The mixtureis concentrated on a Savant Speedvac to give a yellow solid. The solidis triturated with EtOAc, filtered and the filtrate is evaporated togive a yellow solid. This is dissolved in 2 mL water loaded onto apreparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mmI.D., particle size S-5 micron, 12 nM) and eluted at 30 mL/min with agradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5 min. Thenheld at 10:90 until 7 min. Fractions containing product are combined andconcentrated on a Savant Speedvac to yield[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid as awhite solid: [M−1]⁻=269.

EXAMPLE 42 5-(2,4-Dimethoxyphenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-onepotassium salt

A. (2,4-Dimethoxyphenylamino)-acetic acid methyl ester

To a mixture of 1.53 g (10 mmol) of 2,4-dimethoxyaniline and 2.76 g (20mmol) of potassium carbonate in 10 mL of DMF are added 1.53 g (10 mmol)of methyl bromoacetate. The mixture is stirred at 60° C. for 3 h, thenallowed to cool to RT. The mixture is poured into water and extractedwith EtOAc. The organic phase is washed with water, brine and dried overanhydrous Na₂SO₄. The solvent is removed under reduced pressure and theresidue is chromatographed using CH₂Cl₂ as the eluant to give(2,4-dimethoxyphenylamino)-acetic acid methyl ester as an oil: ¹H-NMR(CDCl₃) δ 6.46 (d, J=2.20, 1H), 6.41-6.38 (m, 2H), 3.91 (s, 2H), 3.84(s, 3H), 3.77 (s, 3H), 3.75 (s, 3H).

B. N-(t-Butoxycarbonylsulfamoyl)-N-(2,4-dimethoxyphenyl)glycine methylester

To a solution of 1.15 g (8.08 mmol) of chlorosulfonyl isocyanate in 10mL of CH₂Cl₂ is added dropwise a solution of 598 mg (8.08 mmol) oft-butanol in 2 mL of CH₂Cl₂. The solution is stirred at RT for 45 min,then a solution of 1.3 g (5.8 mmol) of the title A compound,(2,4-dimethoxyphenylamino)-acetic acid methyl ester and 1.2 g (11.9mmol) of TEA in 4 mL of CH₂Cl₂ is added dropwise. The mixture is stirredat RT for 90 min, then washed with water. The organic phase is driedover anhydrous Na₂SO₄ and the solvent is removed under reduced pressure.The residual oil is purified by chromatography using 10% EtOAc in CH₂Cl₂as the eluant to giveN-(t-butoxycarbonylsulfamoyl)-N-(2,4-dimethoxy-phenyl)glycine methylester as a thick yellow oil: ¹H-NMR (CDCl₃) δ 7.57 (d, J=9.19, 1H), 7.19(s, 1H), 6.51-6.46 (m, 2H), 4.55 (br s, 2H), 3.82 (s, 3H), 3.80 (s, 3H),3.71 (s, 3H), 1.53 (s, 9H); [M−1]⁻=403.

C. N-Sulfamoyl-N-(2,4-dimethoxyphenyl)glycine methyl ester

A solution of 1.7 g (4.2 mmol) of the title B compound,N-(t-butoxycarbonyl-sulfamoyl)-N-(2,4-dimethoxyphenyl)glycine methylester in 9 mL of TFA/CH₂Cl₂ (1:1) is stirred at RT for 30 min. Thesolvent is removed under reduced pressure. CH₂Cl₂ is added to theresidue and the solvent is removed under reduced pressure. The resultingoil is purified by chromatography using 10% EtOAc in CH₂Cl₂ as theeluant to afford N-sulfamoyl-N-(2,4-dimethoxyphenyl)glycine methyl esteras an oil which crystallizes on standing: mp=100-103° C.; ¹H-NMR (CDCl₃)δ 7.50 (d, J=8.09, 1H), 6.51-6.44 (m, 2H), 4.98 (br s, 2H), 3.84 (s,3H), 3.81 (s, 3H), 3.75 (s, 3H).

D. 5-(2,4-Dimethoxyphenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-onepotassium salt

To a solution of 980 mg (3.22 mmol) of the title C compound,N-sulfamoyl-N-(2,4-dimethoxyphenyl)glycine methyl ester in 15 mL of THFare added dropwise 3.0 mL of a 1.0M solution of potassium t-butoxide inTHF. The mixture is stirred at RT for 4 h. The resulting precipitate isfiltered and washed with THF. The soild is dried in vacuo to give5-(2,4-dimethoxyphenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one potassiumsalt as a white solid: mp>260° C.; ¹H-NMR (DMSO-d₆) δ 7.34 (d, J=8.66,1H), 6.57 (d, J=2.64, 1H), 6.47 (dd, J=8.66, 3.01, 1H), 3.91 (s, 2H),3.75 (s, 3H), 3.74 (s, 3H); [M−1]⁻=271; Anal. Calcd forC₁₀H₁₁N₂O₅SK+0.3H₂O C, 38.04; H, 3.70; N, 8.87; Found C, 37.93; H, 3.42;N. 8.49.

EXAMPLE 43N-Benzyl-2-[3-methyl-4(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenoxy]-acetamide

A. (3-Methyl-4-nitrophenoxy)-acetic acid t-butyl ester

A mixture of 1.53 g (10 mmol) of 3-methyl-4-nitrophenol, 1.95 g (10mmol) of t-butyl bromoacetate and 2.76 g (20 mmol) of potassiumcarbonate in 10 mL of DMF are stirred at RT for 2 h. Water is added andthe mixture is extracted with EtOAc and the organic phase is washed withwater and brine, and dried over anhydrous Na₂SO₄. The solvent is removedunder reduced pressure and the residual oil is filtered through a pad ofsilica gel using CH₂Cl₂ as the eluant to give(3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester as an oil: ¹H-NMR(CDCl₃) δ 8.08 (d, J=9.56, 1H), 6.82-6.75 (m, 2H), 4.58 (s, 2H), 2.63(s, 3H), 1.49 (s, 9H); Anal. Calcd for C₁₃H₁₇NO₅ C, 58.42; H, 6.41; N,5.24; Found C, 58.04; H, 6.51; N, 5.09.

B. (4-Amino-3-methylphenoxy)-acetic acid t-butyl ester

A solution of 2.35 g (8.8 mmol) of the title A compound,(3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester in 40 mL of EtOH ishydrogenated at 45 psi for 18 h in the presence of 10% Pd/C. Thecatalyst is removed by filtration through Celite and the filtrate isconcentrated to give (4-amino-3-methylphenoxy)-acetic acid t-butyl esteras an oil: ¹H-NMR (CDCl₃) δ 6.68 (br s, 1H), 6.61 (s, 2H), 4.43 (s, 2H),2.15 (s, 3H), 1.48 (s, 9H); [M+1]⁺=238.

C. (4-t-Butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methylester

To a mixture of 2.1 g (8.9 mmol) of the title B compound,(4-amino-3-methylphenoxy)-acetic acid t-butyl ester and 2.44 g (17.7mmol) of potassium carbonate in 8 mL of DMF are added 1.76 g (11.5 mmol)of methyl bromoacetate. The mixture is stirred at 60° C. for 1 h, thenallowed to cool to RT. The mixture is poured into water and extractedwith EtOAc. The organic phase is washed with water and brine, and driedover anhydrous Na₂SO₄. The solvent is removed under reduced pressure andthe residue is chromatographed using CH₂Cl₂ as the eluant to afford(4-t-butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methyl esteras an oil (contaminated with approx 25% of dialkylated product): ¹H-NMR(CDCl₃) δ 6.76-6.64 (m, 2H), 6.40 (d, J=8.46, 1H), 4.43 (s, 2H), 3.91(s, 2H), 3.78 (s, 3H), 2.19 (s, 3H), 1.48 (s, 9H).

D.N-(t-Butoxycarbonylsulfamoyl)-N-(4-t-butoxycarbonylmethoxy-2-methylphenylamino)glycinemethyl ester

To a solution of 1.17 g (8.2 mmol) of chlorosulfonyl isocyanate in 10 mLof CH₂Cl₂ is added dropwise a solution of 610 mg (8.2 mmol) of t-butanolin 5 mL of CH₂Cl₂. The solution is stirred at RT for 45 min, then asolution of 1.96 g (6.3 mmol) of the title C compound,(4-t-butoxycarbonylmethoxy-2-methylphenylamino)-acetic acid methyl esterand 1.1 g (10.9 mmol) of TEA in 8 mL of CH₂Cl₂ is added dropwise. Themixture is stirred at RT for 5 h, then washed with water. The organicphase is dried over anhydrous Na₂SO₄, and the solvent is removed underreduced pressure. The residual oil is purified by chromatography using10% EtOAc in CH₂Cl₂ as the eluant to giveN-(t-butoxycarbonylsulfamoyl)-N-(4-t-butoxycarbonyl-methoxy-2-methylphenylamino)glycinemethyl ester as an oil: ¹H-NMR (CDCl₃) δ 7.42 (d, J=8.67, 1H), 6.79-6.68(m, 2H), 4.52 (q, 2H), 4.49 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 1.49(s, 9H); [M−1]⁻=487.

E. N-Sulfamoyl-N-(4-(methoxycarbonylmethylamino)-3-methylphenoxy-aceticacid

A solution of 630 mg (1.29 mmol) of the title D compound,N-(t-butoxycarbonyl-sulfamoyl)-N-(4-t-butoxycarbonylmethoxy-2-methylphenylamino)glycinemethyl ester in 6 mL of TFA/CH₂Cl₂ (1:1) is stirred at RT for 30 min.The solvent is removed under reduced pressure. CH₂Cl₂ is added to theresidue and the solvent is removed under reduced pressure to giveN-sulfamoyl-N-(4-(methoxycarbonyl-methylamino)-3-methylphenoxy-aceticacid as a sticky white solid: ¹H-NMR (DMSO-d₆) δ 7.32 (d, J=8.83, 1H),7.01 (br s, 2H), 6.80-6.68 (m, 2H), 4.66 (s, 2H), 4.24 (broad d,J=22.80, 2H), 3.59 (s, 3H), 2.34 (s, 3H).

F. {1-[4-(Benzylcarbamoylmethoxy)-2-methylphenyl]-sulfamoyl}-acetic acidmethyl ester

To a solution of 406 mg (1.22 mmol) of the title E compound,N-sulfamoyl-N-(4-(methoxycarbonylmethylamino)-3-methylphenoxy-aceticacid, 234 mg (1.22 mmol) of EDCl and 167 mg (1.22 mmol) of HOAt in 4 mLof DMF are added 131 mg (1.22 mmol) of benzylamine. The mixture isstirred at RT for 18 h, then EtOAc is added. The organic mixture iswashed with aqueous 10% NaHCO₃, 1 N aqueous HCl, water and brine. Theorganic solution is dried over anhydrous Na₂SO₄, and the solvent isremoved under reduced pressure. The residual oil is chromatographedusing 15% EtOAc in CH₂Cl₂ then 50% EtOAc in CH₂Cl₂ as the eluant to give(1-[4-(benzylcarbamoylmethoxy)-2-methylphenyl]-sulfamoyl}-acetic acidmethyl ester as a foam: ¹H-NMR (CDCl₃) δ 7.53 (d, J=8.46, 1H), 7.39-7.25(m, 5H), 6.82 (d, J=2.94, 1H), 6.72 (dd, J=11.39, 2.94, 1H), 5.15 (s,2H), 4.55 (d, J=5.88, 2H), 4.51 (s, 2H), 3.78 (s, 3H), 2.37 (s, 3H);[M−1]=420.

G.N-Benzyl-2-[3-methyl-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenoxy]-acetamide

To a solution of 180 mg (0.427 mmol) of the title F compound{1-[4-(benzyl-carbamoylmethoxy)-2-methylphenyl]-sulfamoyl}-acetic acidmethyl ester in 2 mL of THF is added dropwise 1.0M solution of potassiumt-butoxide in THF (0.42 mL). The mixture is stirred at RT for 5 h andthe solvent is removed under reduced pressure. To the resulting gum areadded 3 mL of water and the resulting solution is washed with MTBE. Theaqueous layer is acidified with 2N aqueous HCl and the mixture isextracted with EtOAc. The organic solution is dried over anhydrousNa₂SO₄, and the solvent is removed under reduced pressure to giveN-benzyl-2-[3-methyl-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenoxy]-acetamideas a beige foam: mp=70-90° C.; ¹H-NMR (CDCl₃) δ 7.43-7.25 (m, 7H), 6.94(t, 1H), 6.87-6.78 (m, 2H), 4.59 (s, 2H), 4.56 (d, J=5.88, 2H), 4.30 (s,2H), 2.39 (s, 3H); [M−1]⁻=388; Anal. Calcd for C₁₈H₁₉N₃O₅S C, 55.52; H,4.92; N, 10.79; Found: C, 55.45; H, 4.92; N, 10.50.

EXAMPLE 443-[3-Hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione

A. 3-Benzyloxy-4-nitrobenzaldehyde

3-Hydroxy-4-nitro-benzaldehyde (4.68 g, 28 mmol) is dissolved in DMF (27mL) and to the solution is added with stirring powdered potassiumcarbonate (4.27 g, 30.1 mmol) and benzyl bromide (3.34 mL, 28.1 mmol).The mixture is stirred at RT overnight, diluted with water (200 mL) andextracted three times with EtOAc. The organic extracts are washed with10% potassium carbonate and brine, dried over anhydrous MgSO₄,decolorized with charcoal, filtered and evaporated to give3-benzyloxy-4-nitro-benzaldehyde as an oil which is used in the nextstep without purification.

B. 3-Benzyloxy-4-nitro-benzyl alcohol

To a cold (ice-water) solution of the title A compound,3-benzyloxy-4-nitro-benzaldehyde (6.13 g, 23.8 mmol) in methanol (60 mL)is added in portions with stirring sodium borohydride (906 mg, 24 mmol)and the mixture is allowed to warm up to RT overnight. The mixture isevaporated to dryness at aspirator pressure and the residue istriturated with 2N aqueous HCl and extracted 3 times with EtOAc. Theorganic extracts are washed with brine, dried over anhydrous MgSO₄,filtered and evaporated to give 3-benzyloxy-4-nitro-benzyl alcohol whichsolidifies on standing at RT under vacuum.

C. 3-Benzyloxy-4-nitro-benzyl alcohol p-tolune sulfonic acid ester

A solution of the title B compound, 3-benzyloxy-4-nitro-benzyl alcohol(0.519 g, 2 mmol) in THF (8 mL) is cooled to 0° C. with stirring undernitrogen and lithium bis(trimethylsilyl)-amide (1 M in hexane, 2 mL, 2mmol) is added dropwise over a period of 5 min. The mixture is stirredat 0° C. for 15 min and p-toluene sulfonyl chloride (382 mg, 2 mmol) isadded all at once. The mixture is stirred at 0° C. for 15 min andquenched with saturated aqueous NH₄Cl (5 mL). The mixture is extractedtwice with EtOAc and the extracts are washed with water and brine, thendried over anhydrous MgSO₄, filtered and evaporated to give3-benzoyloxy-4-nitro-benzyl alcohol p-toluene sulfonic acid ester as aviscous oil: ¹H-NMR δ 7.78 (m, 3H), 7.5-7.3 (m, 7H), 7.05 (s, 1H), 6.88(d, 2H), 5.2 (s, 2H), 5.08, (s, 2H) 2.42 (s, 3H).

D. 3-Benzyloxy-4-nitro-benzyl iodide

To a solution of the title C compound, 3-benzyloxy-4-nitro-benzylalcohol p-toluene sulfonic acid ester (8.57 g, 20.7 mmol) in acetone(126 mL) is added with stirring a solution sodium iodide (7.77 g, 51.8mmol) in acetone (63 mL) all at once. The mixture is stirred at RTovernight and evaporated. The residue is triturated with water,extracted twice with EtOAc and the extracts are washed with water andbrine, then dried over anhydrous MgSO₄ and evaporated. The residue ispurified by chromatography on silica gel column (2×10 cm, onEtOAc-hexane, 1:1) to give of 3-benzyloxy-4-nitro-benzyl iodide whichsolidifies on standing at RT: ¹H-NMR δ 7.81 (d, 1H), 7.1 (s, 1H), 7.0(d, 1H), 7.5-7.3 (m, 5H), 5.23 (s, 2H), 4.39 (s, 2H).

E. 2-(3-Benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic aciddimethyl ester

Sodium hydride (60% in mineral oil, 729 mg, 18.22 mmol) is washed twicewith dry hexane and suspended in DMF (15 mL). To the suspension is addeddropwise a solution of t-butoxycarbonylamino-malonic acid dimethyl ester(4.92 g, 19.9 mmol) in DMF (15 mL) over a period of 10 min. The mixtureis stirred at RT for 40 min and a solution of the title D compound,3-benzyloxy-4-nitro-benzyl iodide (6.23 g, 16.9 mmol) in DMF (15 mL) isadded dropwise over a period of 10 min and the mixture is stirred at RTovernight. The mixture is diluted with water (200 mL) and extracted 3times with EtOAc. The organic extracts are washed with water and brine,dried over anhydrous MgSO₄, filtered and evaporated. The residue iscrystallized from ether-hexane to give2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic aciddimethyl ester: mp=114-116° C.

F. 3-(3-Benzyloxy-4-nitro-phenyl)-2-t-butyloxycarbonylamino-propionicacid methyl ester

To a solution of the title E compound,2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic aciddimethyl ester (6.98 g, 14.3 mmol) in DMSO (68 mL) and water (1.46 mL)sodium chloride (0.85 g, 14.6 mmol) is added and the mixture isgradually heated to 150° C. for 1 h. The mixture is cooled to RT,diluted with water (300 mL) and extracted 3 times with EtOAc. Theorganic extracts are washed with water and brine, dried over anhydrousMgSO₄, decolorized with charcoal, filtered and evaporated. The residueis purified by chromatography (silica gel column, 6×30 cm, onEtOAc-hexane 1:1) to give3-(3-Benzyloxy-4-nitro-phenyl)-2-tert-butyloxycarbonylamino-propionicacid methyl ester as a crystalline solid: mp=104-105° C.

G. 3-(3-Benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester

A solution of the title F compound,3-(3-benzyloxy-4-nitro-phenyl)-2-t-butyloxycarbonylamino-propionic acidmethyl ester (733 mg, 1.7 mmol) in a mixture of CH₂Cl₂-trifluoroaceticacid (1:1, 7 mL) is stirred at RT for 30 min, then evaporated. Theresidue is partitioned between EtOAc and saturated aqueous NaHCO₃. Thelayers are separated and the aqueous layer is extracted once more withEtOAc. The combined organic extracts are washed with brine, dried overanhydrous MgSO₄, filtered and evaporated to give3-(3-benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester as aviscous yellow oil.

H. 2-(2-Amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)propionic acidmethyl ester

A mixture of the title G compound,3-(3-benzyloxy-4-nitro-phenyl)-2-amino-propionic acid methyl ester (597mg, 1.7 mmol), isatoic anhydride (278 mg, 1.7 mmol) and pyridine (5 mL)is heated with stirring at 80° C. for 7 h and allowed to cool to RTovernight. The mixture is evaporated to dryness, the residue isdissolved in EtOAc and the solution is washed with water and brine,dried over anhydrous MgSO₄, filtered and evaporated. The residue ispurified by chromatography (silica gel column, 3×20 cm, onEtOAc-hexane-methanol, 8:12:2) to give2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acidmethyl ester: ¹H-NMR δ 7.815 (d, 1H), 6.294 (s, 1H), 6.825 (d, 1H),7.384-7.206 (m, 7H), 6.699-6.577 (m, 3H), 5.532 (br s, 2H), 5.093-5.039(m, 3H), 3.749 s, 3H), 3.403-3.175 (m, 2H).

I. 2-(2-Amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionicacid

To a solution of the title H compound,2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acidmethyl ester (388 mg, 0.863 mmol) in methanol (8 mL) is added 1N aqueousNaOH (1.73 mL, 1.73 mmol) and the mixture is stirred at RT for 2 h andevaporated. The residue is dissolved in water (20 mL) and the solutionis washed twice with EtOAc. The aqueous layer is neutralized with 1Naqueous HCl (1.73 mL) and extracted three times with EtOAc. The organicextracts are washed with brine, dried over anhydrous MgSO₄, decolorizedwith charcoal, filtered and evaporated to give2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acidas a viscous yellow oil: [M+1]⁺=436, [M−1]⁻=434.

J.3-(3-Benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione

To a solution of the title I compound,2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid(317 mg, 0.728 mmol) in CH₂Cl₂ (10 mL) is added HOBt (111.5 mg, 0.728mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDAC.HCl, 140 mg, 0,72 mmol) and the mixture is stirred at RT for 4 hand evaporated. The residue is partitioned between EtOAc and water andthe organic solution is washed with 1N aqueous HCl, water, saturatedaqueous NaHCO₃ and brine, dried over anhydrous MgSO₄, decolorized andevaporated to a small volume. The precipitated product is collected byfiltration and dried to give3-(3-benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione:mp=243-245° C.

K.3-(4-Amino-3-benzyloxy-benzyl)-3,4-dihydro-1H-benzo[-1,4]diazepine-2,5-dione

A solution of the title J compound,3-(3-benzyloxy-4-nitro-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione(196 mg, 0.47 mmol) in EtOAc-methanol (1:1, 44 mL) is hydrogenated overplatinum oxide (22 mg) at atmospheric pressure for 1 h. The catalyst isfiltered off and the filtrate is evaporated to dryness to give3-(4-amino-3-benzyloxy-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dioneas a foam: [M+1]⁺=388.

L.2-Benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenylamino]-aceticacid ethyl ester

To a solution of the title K compound,3-(4-amino-3-benzyloxy-benzyl)-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione(190 mg, 0.47 mmol) in THF (1 mL) is added ethyl glyoxalate (50% intoluene, 0.120 mL, 0.61 mmol) and the mixture is stirred at RT for 30min. The mixture is diluted with methanol-acetic acid (9:1, 4 mL) andsolid sodium cyanoborohydride (32 mg, 0.52 mmol) is added at once andthe mixture is stirred at RT overnight. The mixture is evaporated todryness the residue is extracted with EtOAc, washed with saturatedaqueous NaHCO₃, and brine, dried and evaporated. The residue is purifiedby chromatography (silica gel column, 2×20 cm, on EtOAc-hexane-methanol6:4:1) to give2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenylamino]-aceticacid ethyl ester as a white crystalline solid: mp=156-158° C.

M.N-[2-Benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[t-butyloxycarbonylaminosulfonyl]-amino-aceticacid ethyl ester

A solution of t-butyloxycarbonylaminosulfonyl chloride in CH₂Cl₂ (1 Msolution) is prepared by dissolving t-butyl alcohol (0.35 mL, 3.66 mmol)in CH₂Cl₂ (2.6 mL), cooling the solution to 0° C., adding dropwise withstirring chlorosulfonyl isocyanate (0.32 mL, 3.68 mmol) and stirring themixture at 0° C. for 1 h. The above reagent (0.314 mL, 0.314 mmol) isadded dropwise to a solution of the title L compound,2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenylamino]-aceticacid ethyl ester (92 mg, 0.194 mmol in CH₂Cl₂ (2 mL) at 0° C. withstirring. The resulting solution is allowed to reach RT and stirredovernight. The mixture is diluted with CH₂Cl₂, washed with water, 1Naqueous HCl, saturated aqueous NaHCO₃, and brine, dried over anhydrousMgSO₄, filtered and evaporated to giveN-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[t-butyloxycarbonylamino-sulfonyl]-amino-aceticacid ethyl ester: [M+1]⁺=653.

N.N-[2-Benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-aceticacid ethyl ester

The title M compound,N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[t-butyloxycarbonylaminosulfonyl]-amino-aceticacid ethyl ester (124 mg, 0.19 mmol) is dissolved inCH₂Cl₂-TFA-triethylsilane (2.5:7:0.5, 1.5 mL) and the solution isstirred at RT for 1 h and evaporated. The residue is dissolved in EtOAcand the solution is washed twice with saturated aqueous NaHCO₃ andbrine, dried over anhydrous MgSO₄, filtered and evaporated to giveN-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-aceticacid ethyl ester as a foam: [M+1]⁺=553.

O.3-[3-Benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione

To a solution of the title N compound,N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-aceticacid ethyl ester (93 mg, 0.168 mmol) in THF is cooled to 0° C. andtreated dropwise with a solution of potassium t-butoxide in THF (1M,0.244 mL, 0.244 mmol). After stirring at 0° C. for 30 min, additionalpotassium t-butoxide solution is added and stirring continued foranother 1 h. The resulting suspension of fine solids is centrifuged, thesupernatant is decanted and the cake of solids is suspended in EtOAc andcentrifuged. The supernatant is decanted and the cake of solids istriturated with EtOAc and 2N aqueous HCl. The EtOAc layer is washed withbrine, dried over anhydrous MgSO₄, decolorized with charcoal, filteredand evaporated to give3-[3-benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dioneas a foam: [M+1]⁺=507.

P.3-[3-Hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione

A solution of3-[3-benzyloxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione(452 mg, 0.89 mmol) in ethanol-acetic acid (2:1, 12 mL) is hydrogenatedover 10% palladium on charcoal catalyst (106 mg) at 50 psi for 24 h. Thecatalyst is filtered and the filtrate is evaporated to dryness. Theresidue is purified by LC-MS, on a Gilson-Micromass instrument using aPhenominex Luna, 5μ, 60×21.2 mm, C-8 column, a gradient of 5% to 100%over 8 min with solvent A (water, 0.1% trifluoroacetic acid) and B(MeCN, 0.1% trifluoroacetic acid) with flow rate 20 mL/min, UV detectorat 215 nm and cone voltage setting at 30 V. The purification isconducted with several runs with 50 mg of crude material being used ineach run (approximately 16 runs). Pure fractions are pooled andevaporated to dryness, the residue is dissolved in water-MeCN and thesolution is filtered and the filtrate is concentrated to give3-[3-hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dioneas an amorphous solid: mp=180° C.; [M+1]⁺=417.

EXAMPLE 45 5-(4-Iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A. N-(2-Trimethylsilylethoxycarbonyl-sulfamoyl)-N-(4-iodo-phenyl)glycinemethyl ester

Chlorosulfonylisocyanate (3.97 mL, 45.6 mmol) is added to CH₂Cl₂ (50 mL)in a dry 300 mL Schlenk flask under argon balloon, and cooled withstirring in an ice/salt/water bath. Trimethylsilylethanol (6.53 mL, 45.6mmol) is added to this solution and stirred while maintaining thecooling for 1 h. Then a solution (4-Iodophenylamino)acetic acid methylester (4.43 g, 15.2 mmol, obtained by alkylation of 4-iodoaniline usingthe method of Tohru Fukuyama et. al., Tet. Lett. 1997, 38 (33), 5831-34)and TEA (8.69 mL, 62.32 mmol) in CH₂Cl₂ (50 mL) is rapidly cannulatedinto this above mentioned stirred, cooled solution. After 30 min, thereaction is poured into 400 mL of 1N aqueous HCl and extracted withEtOAc. The organic layer is washed with 1N aqueous HCl, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue ischromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a30 mL/min gradient elution of 5:95 (EtOAc:CH₂Cl₂) to 10:90 over 15 min.Fractions containing product are combined and evaporated to give an oilwhich on standing in a high vacuum solidified to yieldN-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(4-iodo-phenyl)glycinemethyl ester as a yellow solid.

B. 5-(4-Iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

Tetrabutylammonium fluoride (6.39 g, 24.48 mmol) is added to a solutionof the title A compound,N-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(4-iodo-phenyl)glycinemethyl ester (3.15 g, 6.12 mmol) in freshly distilled tetrahydrofuran(60 mL). The reaction is stirred under argon and heated at 90° C. Thereaction is monitored by reverse phase HPLC (YMC CombiScreen Pro C18,50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/minwith a gradient of 90:10 (0.1% TFA in water: MeCN) to 10:90 at 7.0 min.Starting material has a retention time of 4.88 min and the product has aretention time of 2.83 min. After 24 h, the reaction is poured into 500mL of 1N aqueous HCl and extracted with EtOAc. The organic solution istreated with Na₂SO₄ and charcoal, filtered through celite andconcentrated to give an oil. Crystallization from EtOAc/hexane (and someadditional charcoal) yields5-(4-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light yellowpowder: mp=191-193° C., [M−H]⁻=336.8.

EXAMPLE 46(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid benzyl ester

A.5-(4-Iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title compound of Example 45,5-(4-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (355.9 mg, 1.05mmol) is dissolved in THF (20 mL) in a 40 mL capacity septum cappedvial, and stirred under argon balloon. Triphenylphosphine (552 mg, 2.11mmol) is added as a solid and stirred until dissolved, then4-methyoxybenzyl alcohol (0.156 mL, 1.26 mmol) is added by syringe. Thestirred reaction is cooled in an ice bath, and disopropylazodicarboxylate (0.415 mL, 2.11 mmol) is added slow dropwise bysyringe. After two h, the reaction is concentrated in vacuo and theresidue is taken up in CH₂Cl₂. Chromatography on a 35 g silica gelRediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 10:90(EtOAc:hexane) to 30:70 over 15 min gives5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a white solid. ¹H-NMR (300 MHz, CDCl3) 3.80 (s, 3H), 4.37 (s, 2H),4.79 (s, 2H), 6.89 (d, J=7.5, 2H, aryl), 7.03 (d, J=7.5, 2H), 7.41 (d,J=7.5, 2H), 7.73 (d, J=7.5, 2H).

B.(S)-2-t-Butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester

Onto zinc foil (99.9% Aldrich 35, 602-6, 775 mg, 11.85 mmol) cut insmall pieces is added DMF (freshly distilled from CaH₂ under argon, 4.5mL) and 1,2-dibromoethane (0.033 mL, 0.38 mmol) under argon. The mixtureis heated at 50° C. for 10 min, then allowed to cool and trimethylsilylchloride (0.19 mL, 0.153 mmol) is added. The reaction is stirred for 25min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acidbenzyl ester (Fluka, 2.18 g, 5.37 mmol) in DMF (10 mL) is added. After15 min, the mixture is decanted into a solution of the title A compound,5-(4-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(1.75 g, 3.82 mmol), tri-o-tolylphosphine (232.5 mg, 0.764 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (175 mg, 0.191 mmol) in DMF(13 mL). After stirring for 1.5 h, the resulting reaction mixture ispoured onto a mixture of saturated aqueous ammonium chloride (200 mL)and water (200 mL) and extracted with EtOAc (2×250 mL). The organicsolution is washed with water (1×200 mL) and brine (1×200 mL), thenfiltered through celite to removed a strong gray precipitate. Thefiltrate is dried over anhydrous Na₂SO₄, filtered and concentrated togive a dark red brown oil. This is chromatographed on a 110 g silica gelRediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100(EtOAc:CH₂Cl₂) to 10:90 over 25 min. Fractions containing product arecombined and concentrated to yield(S)-2-t-butoxycarbonylamino-3-(4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester as a white solid after tritruration with Et₂O:[M+NH₄]⁺=627.0, [M−HCO₂]⁻=654.1.

C.(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid benzyl ester

The title B compound,(S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (40 mg, 0.066 mmol) is dissolved in TFA (1.32 mL)containing t-butyidimethylsilane (0.033 mL, 0.198 mmol) in a 1 dramvial. The reaction is monitored by reverse phase HPLC (YMC CombiScreenPro C18, 50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 at 7.0min. Starting material has a retention time of 4.97 min and a new peakhas a retention time of 3.09 min, the starting material without thet-butoxylcarbonyl group as an “intermediate”, [M+H]⁺=510. After 25 minat RT, the reaction is heated at 80° C. for an additional 25 min. A newpeak by HPLC has a retention time of 2.02 min, corresponding to thedesired product. The reaction is cooled, filtered through florisil toremove a black precipitate and concentrated on a Savant Speedvac. Theresulting residue is triturated with Et₂O to give a white solid. Thismaterial is purified on a preparative reverse phase HPLC column (YMCCombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) intwo equal aliquots and eluted at 30 mL/min with a gradient of 90:10(0.1% TFA in water:MeCN) 10:90 over 5.0 min, then held at 10:90 until 7min. Fractions containing product are combined and concentrated on aSavant Speedvac to yield(S)-2-amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid benzyl ester as a white foam: [M−1]⁻=388.0.

EXAMPLE 47(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid

A.(S)-2-t-Butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid

The title B compound in Example 46,(S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (107 mg, 0.176 mmol) is dissolved in a 1:1 mixture ofEtOAc:EtOH (50 mL) in a 200 mL Parr bottle. 10% Palladium on carbon (30mg) is added as a solid and the reaction mixture is hydrogenated on aParr Shaker Apparatus at 41 psi of hydrogen for 2.5 h. The reactionmixture is filtered through celite and concentrated in vacuo to give(S)-2-t-butoxycarbonyl-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid as a white foam: [M−H]⁻=518.1.

B.(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)phenyl]-propionicacid

The title A compound,(S)-2-t-butoxycarbonylamino-3-(4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl)-propionicacid (84.5 mg, 0.163 mmol) is dissolved in TFA (3.26 mL) containingt-butyidimethylsilane (0.081 mL, 0.498 mmol) at RT. The reaction ismonitored by reverse phase HPLC (YMC CombiScreen Pro C18, 50×4.6 mmI.D., particle size S-5 micron, 12 nM) eluting at 3 mL/min with agradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 7.0 min. Thestarting material has a retention time of 3.85 min. After 20 min at RT,the reaction is heated at 80° C. for an additional 45 min. A new peak byHPLC has a retention time of 0.52 min, corresponding to the desiredproduct. The reaction is cooled, filtered through florisil to remove ablack precipitate and concentrated on a Savant Speedvac. The resultingresidue is triturated with Et₂O to give a white solid. This material ispurified on a preparative reverse phase HPLC column (YMC CombiPrep ProC18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in two equalaliquots and eluted at 30 ml/min with a gradient of 100:0 (0.1% TFA inwater:MeCN) to 70:30 over 5.0 min, then to 10:90 by 7 min. Fractionscontaining product are combined and concentrated on a Savant Speedvac,then triturated with 10% dimethylsulfoxide (DMSO) in MeCN to yield(S)-2-amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid as a white solid: [M−1]⁻=298.0.

EXAMPLE 48(S)-2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide

A.((S)-2-{4-[5-(4-Methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester

HOBt (27 mg, 0.175 mmol), pentyl amine (0.020 mL, 0.175 mmol) and1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (37 mg,0.192 mmol) are added to a solution of the title A compound in Example47,(S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid (91 mg, 0.175 mmol) in CH₂Cl₂ (4 mL) and the reaction is stirred atRT for 2 h. The mixture is concentrated and the product is taken up inEtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO₃ and brine.The organic solution is dried over anhydrous MgSO₄, filtered andconcentrated to give a white solid. Chromatography on a 10 g silica gelRediSep (Isco Inc.) column with a 30 mL/min gradient elution of 30:70(EtOAc:hexane) to 60:40 over 10 min yields((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester as a white solid: [M+1]⁺=589.

B.(S)-2-Amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide

A solution of the title A compond,((S)-2-(4-[5-{4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester (64 mg, 0.108 mmol) in CH₂Cl₂ (1 mL) is treated withTFA (1 mL). After 20 min, the solvent is evaporated under stream ofnitrogen. The residue is partitioned between EtOAc and saturated aqueousNaHCO₃, and the organic solution is washed with brine, dried overanhydrous MgSO₄, filtered and concentrated to yield(S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamideas a white solid: [M+1]⁺=489.

C.(S)-2-Acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide

HOBt (16 mg, 0.102 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (21mg, 0.102 mmol) and EDCl (21 mg, 0.112 mmol) are added to a solution ofthe title B compound,(S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide(50 mg, 0.102 mmol) in CH₂Cl₂ (3 mL) and the reaction is stirred at RTfor 2.5 h, then concentrated. The residue is taken up in EtOAc, washedwith 1N aqueous HCl, saturated NaHCO₃ and brine, dried over anhydrousMgSO₄, filtered and concentrated to yield(S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamideas a white foam: [M+1]⁺=678.

D.(S)-2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide

A solution of the title C compound,(S)-2-acetylamino-N-((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide(49 mg, 0.07 mmol) in TFA (1.4 mL) containing t-butyldimethylsilane(0.035 mL, 0.21 mmol) is heated at 80° C. for 1 h. The reaction isconcentrated under nitrogen stream to give an oil which is taken up in60% MeCN in water. Water (1 mL) is added, and the mixture filteredthrough a 0.1 micron Acrodisc filter. The resulting mixture is loadedonto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18,50×20 mm I.D., particle size S-5 micron, 12 nM) in three aliquots andeluted at 30 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to10:90 over 5 min. Then held at 10:90 until 7 min. Fractions containingproduct are combined and concentrated on a Savant Speedvac to yield(S)-2-acetylamino-N-((S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl)-3-phenyl-propionamideas a white solid: [M−1]⁻=556.

EXAMPLE 49[4-(2-{(S)-2-((S)2-Acetylamino-3-phenyl-propionylamino)-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionylamino}ethyl)-phenyl]-acetic

A.(S)-2-Amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester

The title B compound in Example 46,(S)-2-t-butoxycarbonylamino-3-(4-[S-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (100 mg, 0.164 mmol) is dissolved in a mixture of TFA(3.28 mL) and t-butyl-dimethylsilane (0.082 mL, 0.492 mmol) and after 5min the vial is put on a Savant Speedvac to remove solvets. The residueis triturated with Et₂O to give a white solid. This is dissolved inCH₂Cl₂ and washed with 5% aqueous NaHCO₃ solution, dried over anhydrousNa₂SO₄ and evaporated to yield(S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester as an oil.

B.(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester

The title A compound,(S)-2-amino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (79 mg, 0.155 mmol) and(S)-2-acetylamino-3-phenyl-propionic acid (33.7 mg, 0.162 mmol) aredissolved in CH₂Cl₂ (3.1 mL). HOBt (24.8 mg, 0.162 mmol) is added as asolid, followed by EDCl (31.0 mg, 0.162 mmol) and TEA (0.023 mL, 0.162mmol) in a slurry of CH₂Cl₂ (1 mL). After 1 h, EtOAc (100 mL) is addedand the mixture is washed three times with 2N aqueous HCl (50 mL)followed by saturated aqueous NaHCO₃ (50 mL). The EtOAc layer is driedover anhydrous Na₂SO₄ and concentrated to yield(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester as a white powder.

C.(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid

The title B compound,(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (104.3 mg, 0.149 mmol) is dissolved in EtOAc:EtOH(50:50; 250 mL) and put in a Parr Shaker bottle along with 10% Palladiumon carbon (30 mg). This gas in the bottle is evacuated and replaced withhydrogen at 45 psi and shaken for 1.5 h. The reaction mixture isfiltered through celite and concentrated to yield(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid as a light yellow foam.

D.{4-[2-((S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-{4-[5-4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionylamino)ethyl]-phenyl}-aceticacid t-butyl ester

The title C compound,(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid (83.4 mg, 0.137 mmol) is dissolved in DMF (2 mL) and a solution of[4-(2-amino-ethyl)phenyl]-acetic acid t-butyl ester (32.2 mg, 0.137mmol) in CH₂Cl₂ (0.5 mL) is added followed by a solution of HOBt (21.9mg, 0.143 mmol) in DMF:CH₂Cl₂ (50:50, 0.5 mL), and finally EDCl (27.6mg, 0.143 mmol) and TEA (0.020 mL, 0.143 mmol) as a slurry in CH₂Cl₂(0.5 mL). The reaction is mixed well to give a homogeneous solution.After 3 h, EtOAc (100 mL) is added and the reaction is washed threetimes with 2N aqueous HCl (50 mL) and saturated aqueous NaHCO₃ (50 mL).EtOAc layer is dried over anhydrous Na₂SO₄ and concentrated to yield{4-[2-((S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionylamino)-ethyl]-phenyl}-aceticacid t-butyl ester as an oil.

E. [4-(2-{(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino-3-[4(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionylamino}-ethyl)phenyl]-acetic

The title D compound,{4-[2-((S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionylamino)-ethyl]-phenyl}-aceticacid t-butyl ester (85.4 mg, 0.103 mmol) is dissolved in TFA (2.07 mL)containing t-butyidimethysilane (0.051 mL, 0.309 mmol) and heated in asealed vial at 80° C. for 1 h. The solvent is removed on a SavantSpeedvac, and trituration with Et₂O yields a white solid which isdissolved in DMSO:water (1:6, 12 mL) and loaded onto a preparativereverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D.,particle size S-5 micron, 12 nM) in five aliquots and eluted at 30mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 5min. Then held at 10:90 until 7 min. Fractions containing product arecombined and concentrated on a Savant Speedvac to give[4-(2-{(S)-2-((S)-2-acetylamino-3-phenyl-propionylamino)-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionylamino}-ethyl)-phenyl]-aceticas a white powder: [M−1]⁻=648.22.

EXAMPLE 50

The following compounds are prepared analogously to Examples 48 and 49.

Example Chemical Name MS [m/z] 50-1(S)-2-Acetylamino-3-phenyl-N-{(S)-1-(4-phenyl-butylcarbamoyl)-2- [M −H]⁻ = 618[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-propionamide50-22-[4-(2-Benzoylamino-2-{1-carbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-[M + 1]⁺ = 668 2-yl)-phenyl]-ethylcarbamoyl}-ethyl)-phenoxy]-malonicacid 50-3(S)-2-(Biphenyl-4-sulfonylamino)-N-pentyl-3-[4-(1,1,4-trioxo-1,2,5- [M −1]⁻ = 583 thiadiazolidin-2-yl)-phenyl]-propionamide 50-4(S)-2-(Biphenyl-4-sulfonylamino)-N-(4-phenyl-butyl)-3-[4-(1,1,4- [M −1]⁻ = 645 trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide 50-5(S)-2-Benzenesulfonylamino-N-pentyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-[M − 1]⁻ = 507 2-yl)-phenyl]-propionamide 50-6(S)-2-Benzenesulfonylamino-N-(4-phenyl-butyl)-3-[4-(1,1,4-trioxo- [M −1]⁻ = 569 1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide 50-7(S)-2-Benzenesulfonylamino-N-(3,3-diphenyl-propyl)-3-[4-(1,1,4- [M − 1]⁻= 631 trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide 50-8(S)-2-Acetylamino-N-[(S)-2-[3-bromo-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-[M − 1]⁻ = 696, 6982-yl)-phenyl]-1-(4-phenyl-butylcarbamoyl)-ethyl]-3-phenyl- propionamide50-9 (S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-[3-bromo-4-[M + 1]⁺ = 636, 638(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-N-pentyl-propionamide50-10 (S)-2-Benzenesulfonylamino-3-[3-bromo-4-(1,1,4-trioxo-1,2,5- [M +1]⁺ = 649, 651thiadiazolidin-2-yl)-phenyl]-N-(4-phenyl-butyl)-propionamide

EXAMPLE 51(S)-2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide

A. N-(2-Trimethylsilylethoxycarbonyl-sulfamoyl)-N-(3-iodo-phenyl)glycinemethyl ester

To a cooled (ice/salt/water bath) solution of chlorosulfonylisocyanate(3.23 mL, 37.1 mmol) in CH₂Cl₂ (100 mL) is added trimethylsilylethanol(5.32 mL, 37.1 mmol). After 1 h, a solution of(3-Iodo-phenylamino)-acetic acid methyl ester (2.7 g, 9.28 mmol)(obtained by alkylation of 3-iodoaniline using the method of TohruFukuyama et. al., Tett. Lett. 38 (33) pp. 5831-34,1997) and TEA (5.3 mL,38.04 mmol) in CH₂Cl₂ (50 mL) is added and the reaction is stirred for2.5 h. The mixture is poured into 400 mL of 1N aqueous HCl and extractedwith EtOAc. The EtOAc layer is washed with 1N aqueous HCl, dried overanhydrous Na₂SO₄, filtered and concentrated. Chromatography on a 110 gsilica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elutionof 10:90 (EtOAc:hexane) to 40:60 over 55 min gives an oil. Triturationwith Et₂O yieldsN-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(3-iodo-phenyl)glycinemethyl ester as a white solid.

B. 5-(3-Iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

A solution of tetrabutylammonium fluoride (5.88 g, 18.67 mmol) in THF(40 mL) is added a solution of the title A compound,N-(2-trimethylsilylethoxycarbonyl-sulfamoyl)-N-(3-iodo-phenyl)glycinemethyl ester (2.33 g, 4.5 mmol) in THF (50 mL). The reaction is heatedat 90° C. and monitored by reverse phase HPLC (YMC CombiScreen Pro C18,50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/minwith a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 at 7.0 min.Starting material has a retention time of 4.82 min and the product has aretention time of 2.81 min. After 24 h, the reaction is poured into 500mL of 1N aqueous HCl and extracted with EtOAc. The organic solution isdried over anhydrous MgSO₄, filtered and concentrated to give a yellowsolid. Trituration with EtOAc/hexane yields5-(3-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid:(M−H)⁻=336.9.

C.5-(3-Iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

The title B compound,5-(3-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (932 mg, 2.76mmol) is dissolved in tetrahydrofuran (20 mL) in a 40 mL capacity septumcapped vial, stirred under argon balloon. Triphenylphosphine (1.47 g,5.51 mmol) is added as a solid and stirred until dissolved, then4-methyoxybenzyl alcohol (0.688 mL, 5.51 mmol) is added by syringe. Thestirred reaction is cooled in an ice bath, and diethyl azodicarboxylate(0.867 mL, 5.51 mmol) is added slow dropwise by syringe. The reaction isstirred 16 h and then recooled and added more diethyl azodicarboxylate(0.433 mL, 2.26 mmol). After 5H, the reaction is concentrated in vacuo,then taken up in CH₂Cl₂ and chromatographed on a 35 g silica gel RediSepcolumn (Isco, Inc.) with a 30 mL/min gradient elution of 0:100(EtOAc:CH₂Cl₂) for 5 min, then to 5:95 over 35 min. Fractions containingproduct are combined, concentrated and recrystalized with EtOAc/hexanesto yield5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-oneas a white solid: ¹H-NMR (300 MHz, DMSO-d₆) δ 3.76 (s, 3H), 4.79 (s,2H), 4.88 (s, 2H), 6.92 (d, J=7.5, 2H), 7.27 (t, J=7.5, 1H), 7.33 (d,J=7.5, 2H), 7.39 (d, J=7.5, 1H), 7.63 (d, J=7.5, 1H), 7.67 (s, 1H).

D.(S)-2-t-Butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester

Onto zinc foil (99.9% Aldrich 35, 602-6,118.5 mg, 1.813 mmol) is cut insmall pieces is added DMF (freshly distilled from CaH₂ under argon, 0.4mL) and 1,2-dibromoethane (0.006 mL, 0.065 mmol) under argon. Themixture is heated at 50° C. for 10 min, then allowed to cool andtrimethylsilyl chloride (0.003 mL, 0.026 mmol) is added. The reaction isstirred for 25 min and a solution of(R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka,342 mg, 0.844 mmol) in DMF (1 mL) is added. After 1 h, the mixture isdecanted to a solution of the title C compound,5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one(300 mg, 0.65 mmol), tri-o-tolylphosphine (29.9 mg, 0.13 mmol) andtris(dibenzylideneacetone)-dipalladium(0) (29.9 mg, 0.033 mmol) in DMF(2 mL). After stirring for 1.5 h, the resulting reaction mixture ispoured onto water (100 mL), extracted with EtOAc (2×100 mL). Thecombined EtOAc layers are washed with water (1×200 mL) and brine (1×200mL), dried over anhydrous MgSO₄, filtered and concentrated to give ayellow oil. This is chromatographed on a 35 g silica gel RediSep column(Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH₂Cl₂)to 12:88 over 40 min. Fractions containing product are combined andconcentrated to yield(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester as a clear oil: [M+NH₄]⁺=627.0, [M−HCO₂]⁻=654.1.

E.(S)-2-t-Butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid

The title D compound,(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid benzyl ester (187 mg, 0.307 mmol) is dissolved in a 1:1 mixture ofEtOAc:EtOH (50 mL) in a 200 mL Parr bottle. 10% Palladium on carbon (52mg) is added as a solid and the reaction mixture is hydrogenated on aParr Shaker Apparatus at 47 psi of hydrogen for 1.33 h. The reactionmixture is filtered through celite and concentrated in vacuo to give(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionicacid as a white foam: [M−1]⁻=518.1.

F.((S)-2-{3-[5-(4-Methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester

HOBt (46.4 mg, 0.302 mmol), pentyl amine (0.035 mL, 0.302 mmol) and EDCl(63.7 mg, 0.332 mmol) are added to a solution of the title E compound,(S)-2-t-butoxycarbonyl-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl)-propionicacid (157 mg, 0.302 mmol) in CH₂Cl₂ (10 mL) and this is stirred at roomtemperature for 1 h. The reaction is then concentrated in vacuo and theproduct is taken up in EtOAc. The organic solution is successivelywashed with 1N aqueous HCl, saturated aqueous NaHCO₃ solution and brine,dried over anhydrous MgSO₄, filtered and concentrated to yield((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester as a white film.

G.(S)-2-Amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide

A solution of the title F compound,((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamicacid t-butyl ester (156 mg, 0.265 mmol) in CH₂Cl₂ (1 mL) is treated withTFA (1 mL). After 30 min, the solvent is evaporated under stream ofnitrogen. The residue is partitioned between EtOAc and saturated aqueousNaHCO₃. The organic solution is washed with brine, dried over anhydrousMgSO₄ and concentrated to yield(S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamideas a white solid: [M+1]⁺=489.

H.(S)-2-Acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide

HOBt (40.5 mg, 0.264 mmol), (S)-2-acetylamino-3-phenyl-propionic acid(54.7 mg, 0.264 mmol) and EDCl (50.6 mg, 0.264 mmol) are added to asolution of the title G compound,(S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide(129 mg, 0.264 mmol) in CH₂Cl₂ (5 mL) and stirred at RT for 2 h. Thereaction is concentrated and the product is taken up in EtOAc, washedwith 1N aqueous HCl, saturated aqueous NaHCO₃ and brine, dried overmagnesium sulfate, filtered and concentrated to yield(S)-2-acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamideas a white solid: [M+1]⁺=678.

I.(S)-2-Acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide

A solution of the title H compound,(S)-2-acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide(124 mg, 0.183 mmol) in TFA (3 mL) containing t-butyidimethylsilane(0.091 mL, 0.548 mmol) is heated at 80° C. for 30 min, then concentratedunder nitrogen stream to give an oil containing a fine dark suspension.The product is taken up in 60% MeCN in water and water (1 mL) is added.The mixture filtered through a 0.1 micron Acrodisc filter and thefiltrate is loaded onto a preparative reverse phase HPLC column (YMCCombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) infive aliquots and eluted at 30 mL/min with a gradient of 90:10 (0.1% TFAin water:MeCN) to 10:90 over 5 min. Then held at 10:90 until 7 min.Fractions containing product are combined and concentrated on a SavantSpeedvac to yield(S)-2-acetylamino-N-{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamideas a white foam: [M+1]⁺=558.

1. A compound of the formula

wherein R₁ is hydrogen, halogen, hydroxy, alkoxy, carboxy, cyano, nitro,trifluoromethyl, alkynyl, alkylthio, heteroaralkyl, heteroaralkoxy orheteroaryloxy provided that R₁ is located at the 2-position when L₃ is—(CHR)_(s)— in which s is zero; or R₁ is optionally substituted alkyl,alkenyl, optionally substituted amino, aralkyl, aralkoxy, aralkylthio,aryloxy, arylthio or cycloalkyl provided that a monocyclic aryl groupwhich is substituted at the para position with a methylene or ethylenebridged nitrogen containing heterocycle does not constitute part of R₁when (i) R₁ is located at the 2-position and L₃ is —(CHR)_(s)— in whichs is zero; (ii) X and Y each are CH; and (iii) Q₂ is oxygen; or C—R₁ maybe replaced with nitrogen or N→O; or R₁ and R₂ combined together withthe carbon atoms to which R₁ and R₂ are attached form an optionallysubstituted fused 5- to 6-membered aromatic or heteroaromatic ringprovided that R₁ and R₂ are attached to carbon atoms adjacent to eachother; or R₂ is hydrogen, halogen, hydroxy, alkoxy, cyano,trifluoromethyl, nitro, optionally substituted amino, optionallysubstituted alkyl, alkylthio, aralkyl, heteroaralkyl, aralkoxy,heteroaralkoxy, aralkylthio, aryloxy, heteroaryloxy, arylthio orcycloalkyl; or R₂ is —C(O)R₃ wherein R₃ is hydroxy or optionallysubstituted alkoxy; or R₃ is —NR₄R₅ in which R₄ and R₅ are independentlyhydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heterocyclyl, aralkyl or heteroaralkyl; L₁ is a single bond; or L₁is carbon which combined together with R₂ and the carbon atoms to whichL₁ and R₂ are attached form an optionally substituted fused 5- or6-membered aromatic or heteroaromatic ring provided that L₁ and R₂ areattached to carbon atoms adjacent to each other; or L₁ is CH or nitrogenwhich taken together with R₂ and the carbon atoms to which L₁ and R₂ areattached form a fused 5- to 7-membered ring which may be interruptedwith one or two heteroatoms selected from oxygen, nitrogen and sulfurprovided that L₁ and R₂ are attached to carbon atoms adjacent to eachother; or L₁ is CH, oxygen, sulfur or nitrogen and L₂ is carbon whichcombined together with L₁, R₂ and the carbon atoms to which L₁ and R₂are attached form an optionally substituted fused 5- or 6-memberedaromatic or heteroaromatic ring provided that L₁ and R₂ are attached tocarbon atoms adjacent to each other; or L₁ is —CH₂—, oxygen, sulfur or—NR₆— and L₂ is CH which taken together with L₁, R₂ and the carbon atomsto which L₁ and R₂ are attached form a fused 5- to 7-membered ring whichmay be interrupted with one or two heteroatoms selected from oxygen,nitrogen and sulfur wherein R₆ is hydrogen, optionally substitutedalkyl, aralkyl, heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl,carbamoyl, sulfonyl or acyl provided that L₁ and R₂ are attached tocarbon atoms adjacent to each other; L₂ is —(CHR₇)_(n)— wherein R₇ ishydrogen, hydroxy, alkoxy, carboxy, optionally substituted alkyl,cycloalkyl, aryl or heteroaryl; n is zero or an integer from 1 to 4; Zis —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein R₈ is hydrogen, optionally substitutedalkyl, cycloalkyl, aryl or heterocyclyl; R₉ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl,heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,carbamoyl, sulfonyl, acyl or acylamino; m and r are independently zeroor an integer of 1 or 2; Q₁ is hydrogen, optionally substituted alkyl,cycloalkyl, aryl or heterocyclyl provided that (i) Q₁ is not2-phenyloxazol-4-yl when R₁ and R₂ are hydrogen; X and Y each are CH; L₁is a single bond located at the 4-position; L₂ is —(CHR₇)_(n)— wherein nis zero; L₃ is —(CHR)_(s)— wherein s is zero; Z is—(CH₂)_(m)O(CHR₈)_(r)— wherein R₈ is hydrogen, m is zero and r is 2; andQ₂ is oxygen; or (ii) Q₁ is not hydrogen when R₁ and R₂ are hydrogen; Xand Y each are CH; L₁ is a single bond; L₂ is —(CHR₇)_(n)— wherein n iszero; L₃ is —(CHR)_(s)— wherein R is hydrogen and s is 1; Z is—(CHR₈)_(m)— wherein m is zero; and Q₂ is oxygen; or Q₁ isC(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein R_(4a)and R_(5a) are as defined for R₄ and R₅; R₁₀ is optionally substitutedalkyl, cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; q is aninteger of 1 or 2; or Q₁ is a radical of the formula

wherein W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or W₁ is—C(O)R_(3a) in which R_(3a) is hydroxy or optionally substituted alkoxy;or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as definedfor R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₁ is —C(O)—, —S(O)₂— or—(CH₂)_(r)— in which r is as defined for Z; V₁ is hydroxy, alkoxy, aryl,heteroaryl, optionally substituted alkyl or cycloalkyl; or V₁ is—NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined for R₄ and R₅provided that (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;and (ii) Z is —(CHR₈)_(m)— in which m is zero; or Q₁ is a radical of theformula

wherein W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) andR_(5a) are as defined for R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₂is —(CH₂)_(p)— in which p is zero or 1; V₂ is —NR_(4b)C(O)R_(5b),—NR_(4b)C(O)OR_(5b), —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) inwhich R_(4b) and R_(4c) are as defined for R₄, and R_(5b) has a meaningas defined for R₅ provided that (i) L₂ is —(CHR₇)_(n)— in which n is aninteger of 1 or 2; and (ii) Z is —(CHR)_(m)— in which m is zero; or Q₁is a radical of the formula

wherein W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) andR_(5a) are as defined for R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₃is —(CH₂)_(p)— in which p is zero or 1; V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂wherein R_(4b) is as defined for R₄; R₁₂ is hydrogen, aryl,heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl,alkoxy or cycloalkyl; or R₁₂ is —NR_(4c)R_(5b), in which R_(4c) andR_(5b) are as defined for R₄ and R₅ provided that (i) L₂ is —(CHR₇)_(n)—in which n is an integer of 1 or 2; and (ii) Z is —(CHR)_(m)— in which mis zero; L₃ is —(CHR)_(s)— wherein R is hydrogen, carboxy, optionallysubstituted alkyl, cycloalkyl, aryl or heteroaryl; s is zero or aninteger from 1 to 3; Q₂ is oxygen, sulfur or NR₁₃ wherein R₁₃ ishydrogen, hydroxy or lower alkyl; X and Y are —CH—; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 2. The compound according to claim 1 wherein Q₂ is oxygen; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 3. The compound according to claim 2 of the formula

wherein R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl,alkylthio, heteroaralkyl or heteroaralkoxy provided that R₁ is locatedat the 2-position when L₃ is —(CHR)_(s)— in which s is zero; or R₁ isoptionally substituted alkyl, aralkyl, aralkoxy or aryloxy provided thata monocyclic aryl group which is substituted at the para position with amethylene or ethylene bridged nitrogen containing heterocycle does notconstitute part of R₁ when (i) R₁ is located at the 2-position and L₃ is—(CHR)_(s)— in which s is zero; and (ii) X and Y each are CH; R₂ ishydrogen; or R₂ is —C(O)R₃ wherein R₃ is hydroxy or optionallysubstituted alkoxy; or R₃ is —NR₄R₅ in which R₄ and R₅ are independentlyhydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl,aralkyl or heteroaralkyl; L₁ is a single bond; or L₁ is carbon whichcombined together with R₂ and the carbon atoms to which L₁ and R₂ areattached form an optionally substituted fused 5- or 6-membered aromaticor heteroaromatic ring provided that L₁ and R₂ are attached to carbonatoms adjacent to each other; or L₁ is CH or nitrogen which takentogether with R₂ and the carbon atoms to which L₁ and R₂ are attachedform a fused 5- to 7-membered ring which may be interrupted with one ortwo heteroatoms selected from oxygen, nitrogen and sulfur provided thatL₁ and R₂ are attached to carbon atoms adjacent to each other; or L₁ isCH, oxygen, sulfur or nitrogen and L₂ is carbon which combined togetherwith L₁, R₂ and the carbon atoms to which L₁ and R₂ are attached form anoptionally substituted fused 5- or 6-membered aromatic or heteroaromaticring provided that L₁ and R₂ are attached to carbon atoms adjacent toeach other; or L₁ is —CH₂—, oxygen, sulfur or —NR₆— and L₂ is CH whichtaken together with L₁, R₂ and the carbon atoms to which L₁ and R₂ areattached form a fused 5- to 7-membered ring which may be interruptedwith one or two heteroatoms selected from oxygen, nitrogen and sulfurwherein R₆ is hydrogen, optionally substituted alkyl, aralkyl,heteroaralkyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, sulfonyl oracyl provided that L₁ and R₂ are attached to carbon atoms adjacent toeach other; or L₂ is —(CHR₇)_(n)— wherein R₇ is hydrogen; n is zero oran integer of 1 or 2; Z is —(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—,—(CH₂)_(m)S(CHR₈)_(r)— or —(CH₂)_(m)NR₉(CHR₈)_(r)— wherein R₈ ishydrogen or optionally substituted alkyl; R₉ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl; m and r areindependently zero or an integer of 1 or 2; Q₁ is hydrogen, optionallysubstituted alkyl, cycloalkyl, aryl or heterocyclyl provided that (i) Q₁is not 2-phenyloxazol-4-yl when R₁ and R₂ are hydrogen; X and Y each areCH; L₁ is a single bond located at the 4-position; L₂ is —(CHR₇)_(n)—wherein n is zero; L₃ is —(CHR)_(s)— wherein s is zero; and Z is—(CH₂)_(m)O(CHR₈)_(r)— wherein R₈ is hydrogen, m is zero and r is 2; or(ii) Q₁ is not hydrogen when R₁ and R₂ are hydrogen; X and Y each areCH; L₁ is a single bond; L₂ is —(CHR₇)_(n)— wherein n is zero; L₃ is—(CHR)_(s)—wherein R is hydrogen and s is 1; and Z is —(CHR₈)_(m)—wherein m is zero; or Q₁ is —C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or—S(O)_(q)R₁₀ wherein R_(4a) and R_(5a) are as defined for R₄ and R₅; R₁₀is optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkylor heteroaralkyl; q is an integer of 1 or 2; or Q₁ is a radical of theformula

wherein W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or W₁ is—C(O)R_(3a) in which R_(3a) is hydroxy or optionally substituted alkoxy;or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are as definedfor R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₁ is —C(O)— or—(CH₂)_(r)— in which r is as defined for Z; V₁ is hydroxy, alkoxy, aryl,heteroaryl, optionally substituted alkyl or cycloalkyl; or V₁ is—NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined for R₄ and R₅provided that (i) L₂ is —(CHR₇)_(n)— in which n is an integer of 1 or 2;and (ii) Z is —(CHR₈)_(m)— in which m is zero; or Q₁ is a radical of theformula

wherein W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) andR_(5a) are as defined for R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₂is —(CH₂)_(p)— in which p is zero or 1; V₂ is —NR_(4b)C(O)R_(5b),—NR_(4b)C(O)OR_(5b), —NR_(4b)C(O)NR_(4c)R_(5b) or —NR_(4b)S(O)₂R_(5b) inwhich R_(4b) and R_(4c) are as defined for R₄ and R_(5b) has a meaningas defined for R₅ provided that (i) L₂ is —(CHR₇)_(n)— in which n is aninteger of 1 or 2; and (ii) Z is —(CHR₈)_(m)— in which m is zero; or Q₁is a radical of the formula

wherein W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(3a)R_(4a) in which R_(4a) andR_(5a) are as defined for R₄ and R₅; R₁₁ is hydrogen, alkyl or aryl; U₃is —(CH₂)_(p)— in which p is zero or 1; V₃ is —NHC(O)CHR_(4b)NHC(O)R₁₂wherein R_(4b) is as defined for R₄; R₁₂ is hydrogen, aryl,heterocyclyl, aralkyl, heteroaralkyl, optionally substituted alkyl,alkoxy or cycloalkyl; or R₁₂ is —NR_(4c)R_(5b), in which R_(4c) andR_(5b) are as defined for R₄ and R₅ provided that (i) L₂ is —(CHR₇)_(n)—in which n is an integer of 1 or 2; and (ii) Z is —(CHR₈)_(m)— in whichm is zero; L₃ is —(CHR)_(s)— wherein R is hydrogen; s is zero or aninteger from 1 to 3; X and Y each are CH; or a pharmaceuticallyacceptable salt thereof; or a prodrug derivative thereof.
 4. Thecompound according to claim 3 of the formula

wherein R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl,optionally substituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy,heteroaralkyl or heteroaralkoxy; n is zero or an integer of 1 or 2; Z is—(CHR₈)_(m)—, —(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein R₈ is hydrogen; R₉ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl; mand r are independently zero or an integer of 1 or 2; Q₁ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or Q₁ isC(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein R_(4a)and R_(5b) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₀ isoptionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; s is zero or an integer of 1or 2; Q₃ is O, S or —NR_(6a)— wherein R_(6a) is hydrogen, optionallysubstituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl,aryloxycarbonyl, carbamoyl, sulfonyl or acyl; X and Y each are CH; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 5. The compound according to claim 3 of the formula

wherein R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl,optionally substituted alkyl, alkylthio, aralkyl, aralkoxy, aryloxy,heteroaralkyl or heteroaralkoxy; Z is —(CHR₈)_(m)—,—(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein R₈ is hydrogen; R₉ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl or acyl; mand r are independently zero or an integer of 1 or 2; Q₁ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or Q₁ is—C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein R_(4a)and R_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₀ isoptionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; s is zero or an integer of 1or 2; Q₃ is O, S or —NR_(6a)— wherein R_(6a) is hydrogen, optionallysubstituted alkyl, aralkyl, heteroaralkyl, alkoxycarbonyl,aryloxycarbonyl, carbamoyl, sulfonyl or acyl; X and Y are CH; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 6. The compound according to claim 3 wherein R₂ is hydrogen; L₁is a single bond; L₂ is —(CH₂)_(n)— in which n is zero or an integer of1 or 2; or a pharmaceutically acceptable salt thereof; or a prodrugderivative thereof.
 7. The compound according to claim 6 of the formula

wherein R₁ is hydrogen, halogen, hydroxy, alkoxy, trifluoromethyl oralkylthio provided that R₁ is located at the 2-position when s is zero;or R₁ is optionally substituted alkyl, aralkyl, aralkoxy or aryloxyprovided that a monocyclic aryl group which is substituted at the paraposition with a methylene or ethylene bridged nitrogen containingheterocycle does not constitute part of R₁ when (i) R₁ is located at the2-position and s is zero; and (ii) X and Y each are CH; n is zero or aninteger of 1 or 2; s is zero or 1; Z is —(CHF₈)_(m)—,—(CH₂)_(m)O(CHR₈)_(r)—, —(CH₂)_(m)S(CHR₈)_(r)— or—(CH₂)_(m)NR₉(CHR₈)_(r)— wherein R₈ is hydrogen; R₉ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or acyl; mand r are independently zero or an integer of 1 or 2; Q₁ is hydrogen,optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl providedthat (i) Q₁ is not 2-phenyloxazol-4-yl when R₁ is hydrogen; X and Y eachare CH; n is zero; s is zero; and Z is —(CH₂)_(m)O(CHR₈)_(r)— wherein R₈is hydrogen, m is zero and r is 2; or (ii) Q₁ is not hydrogen when R₁ ishydrogen; X and Y each are CH; n is zero; s is 1; Z is —(CHR₈)_(m)—wherein m is zero; or Q₁ is C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or—S(O)_(q)R₁₀ wherein R_(4a) and R_(5a) are independently hydrogen,optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; R₁₀ is optionally substituted alkyl, cycloalkyl, aryl,heterocyclyl, aralkyl or heteroaralkyl; q is an integer of 1 or 2; or Q₁is a radical of the formula

wherein W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; or W₁ is—C(O)R_(3a) in which R_(3a) is hydroxy or optionally substituted alkoxy;or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) and R_(5a) are independentlyhydrogen, optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl,aralkyl or heteroaralkyl; R₁₁ is hydrogen, alkyl or aryl; U₁ is —C(O)—or —(CH₂)_(r)— in which r is as defined for Z; V₁ is hydroxy, alkoxy,aryl, heteroaryl, optionally substituted alkyl or cycloalkyl; or V₁ is—NR_(4b)R_(5b) in which R_(4b) and R_(5b) are as defined for R_(4a) andR_(5a) provided that (i) n is an integer of 1 or 2; and (ii) Z is—(CHR₈)_(m)— in which m is zero; or Q₁ is a radical of the formula

wherein W₂ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) andR_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₁ ishydrogen, alkyl or aryl; U₂ is —(CH₂)_(p)— in which p is zero or 1; V₂is —NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b), —NR_(4b)C(O)NR_(4c)R_(5b) or—NR_(4b)S(O)₂R_(5b) in which R_(4b) and R_(4c) are as defined forR_(4a), and R_(5b) has a meaning as defined for R_(5a) provided that (i)n is an integer of 1 or 2; and (ii) Z is —(CHR₈)_(m)— in which m iszero; or Q₁ is a radical of the formula

wherein W₃ is —C(O)R_(3a) in which R_(3a) is hydroxy or optionallysubstituted alkoxy; or R_(3a) is —NR_(4a)R_(5a) in which R_(4a) andR_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₁ ishydrogen, alkyl or aryl; U₃ is —(CH₂)_(r)— in which r is zero or 1; V₃is —NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for R_(4a); R₁₂is hydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionallysubstituted alkyl, alkoxy or cycloalkyl; or R₁₂ is —NR_(4c)R_(5b) inwhich R_(4c) is as defined for R_(4a), and R_(5b) has a meaning asdefined for R_(5a) provided that (i) n is an integer of 1 or 2; and (ii)Z is —(CHR₈)_(m)— in which m is zero; X and Y each are CH; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 8. The compound according to claim 7 wherein R₁ is bromide; Xand Y each are CH; or a pharmaceutically acceptable salt thereof; or aprodrug derivative thereof.
 9. The compound according to claim 7 whereinn is zero; s is 1; Z is —(CH₂)_(m)— in which m is zero; Q₁ is—C(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein R_(4a)and R_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₀ isoptionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; or a pharmaceuticallyacceptable salt thereof; or a prodrug derivative thereof.
 10. Thecompound according to claim 7 wherein n is an integer of 1 or 2; Z is—(CH₂)_(m)O(CH₂)_(r)— or —(CH₂)_(m)S(CH₂)_(r)— wherein m is zero; r iszero or 1; Q₁ is optionally substituted alkyl, cycloalkyl, aryl orheterocyclyl; or a pharmaceutically acceptable salt thereof; or aprodrug derivative thereof.
 11. The compound according to claim 7wherein n is an integer of 1 or 2; Z is —(CH₂)_(m)NR₉(CH₂)_(r)— whereinR₉ is hydrogen, optionally substituted alkyl, cycloalkyl, aryl,heteroaryl or acyl; m is zero; r is zero or 1; Q₁ is optionallysubstituted alkyl, cycloalkyl, aryl or heterocyclyl; or Q₁ isC(O)NR_(4a)R_(5a), —C(O)R₁₀, —C(O)OR₁₀ or —S(O)_(q)R₁₀ wherein R_(4a)and R_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₀ isoptionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl orheteroaralkyl; q is an integer of 1 or 2; or a pharmaceuticallyacceptable salt thereof; or a prodrug derivative thereof.
 12. Thecompound according to claim 7 wherein n is an integer of 1 or 2; Z is—(CH₂)_(m)— wherein m is zero; Q₁ is a radical of the formula

wherein W₁ is aryl, heteroaryl, aralkyl or heteroaralkyl; R₁₁ ishydrogen, alkyl or aryl; U₁ is —C(O)— or —(CH₂)_(r)— in which r is zero;V₁ is aryl, heteroaryl, optionally substituted alkyl or cycloalkyl; or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 13. The compound according to claim 7 wherein n is 1; Z is—(CH₂)_(m)— wherein m is zero; Q₁ is a radical of the formula

wherein W₂ is —C(O)R_(3a) in which R_(3a) is —NR_(4a)R_(5a), and R_(4a)and R_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₁ ishydrogen; U₂ is —(CH₂)_(p)— in which p is zero; V₂ is—NR_(4b)C(O)R_(5b), —NR_(4b)C(O)OR_(5b), —NR_(4b)C(O)NR_(4c)R_(5b) or—NR_(4b)S(O)₂R_(5b) in which R_(4b) and R_(4c) are as defined forR_(4a), and R_(5b) has a meaning as defined for R_(5a); or apharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 14. The compound according to claim 7 wherein n is 1; Z is—(CH₂)_(m)— wherein m is zero; Q₁ is a radical of the formula

wherein W₃ is —C(O)R_(3a) in which R_(3a) is —NR_(4a)R_(5a), and R_(4a)and R_(5a) are independently hydrogen, optionally substituted alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl or heteroaralkyl; R₁₁ ishydrogen; U₃ is —(CH₂)_(p)— in which p is zero; V₃ is—NHC(O)CHR_(4b)NHC(O)R₁₂ wherein R_(4b) is as defined for R_(4a); R₁₂ ishydrogen, aryl, heterocyclyl, aralkyl, heteroaralkyl, optionallysubstituted alkyl or alkoxy; or R₁₂ is —NR_(4c)R_(5b) in which R_(4c)and R_(5b) are as defined for R_(4a) and R_(5a); or a pharmaceuticallyacceptable salt thereof; or a prodrug derivative thereof.
 15. Thecompound according to claim 1 which is selected from:5-Naphthalen-1-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide;[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-carbamic acidt-butyl ester;5-(4-Aminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-carbamic acidt-butyl ester;3-Phenyl-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-propionamide;5-(3-Iodo-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Amino-benzyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetamide;5-(4-Amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-butyramide;1-Propyl-3-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-urea;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid methylester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;5-(2-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Amino-2-bromo-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetamide;N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-methanesulfonamide;N-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-methanesulfonamide;5-(4-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;Amino-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-aceticacid;2-Amino-N-propyl-2-[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetamide;2-Amino-N-propyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetamide;2,2,2-Trifluoro-N-{propylcarbamoyl-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-methyl}-acetamide;2-Methanesulfonylamino-N-propyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetamide;2-Acetylamino-N-propyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-propionamide;2-Acetylamino-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-malonicacid diethyl ester;2-Amino-N-propyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-propionamide;2-Acetylamino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-propionicacid ethyl ester; Phenyl-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-aceticacid; 1,1-Dioxo-5-phenethyl-1,2,5-thiadiazolidin-3-one;5-[2-(4-Methyl-thiazol-5-yl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[2-(3,4-Dimethoxy-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[2-(2-Chloro-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[2-(4-Amino-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2,2,2-Trifluoro-N-{4-[2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)ethyl]-phenyl}-acetamide;N-{4-[2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-ethyl]-phenyl}-butyramide;3-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic acid;5-[2-(3-Amino-phenyl)-ethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Aminomethyl-naphthalen-1-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(1-Ethyl-2-methyl-1H-benzimidazol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[2-Methyl-1-(3-methyl-butyl)-1H-benzimidazol-5-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Methoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Isobutoxy-quinolin-7-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;{(1-Butylcarbamoyl-3-phenyl-propyl)-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[Butylcarbamoyl-(4-ethyl-phenyl)-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[Butylcarbamoyl-(3-phenoxy-phenyl)-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[Butylcarbamoyl-(4-methoxy-phenyl)-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[(2-Bromo-phenyl)-butylcarbamoyl-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;(Butylcarbamoyl-naphthalen-2-yl-methyl)-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[Butylcarbamoyl-(4-chloro-phenyl)-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{[(3-Benzyloxy-phenyl)-butylcarbamoyl-methyl]-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;{((E)-1-Butylcarbamoyl-3-phenyl-allyl)-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-amino}-aceticacid;N-(1-Butylcarbamoyl-3-phenyl-propyl)-N-(4-(1,1,4-trioxo-1,2,5-thiazodiazolidin-2-ylmethyl)-benzoyl)amino-aceticacid; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-methanesulfonyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-chloro-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-butyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-hydroxymethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-phenethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidbiphenyl-2-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-difluoromethoxy-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-(carboxy-difluoro-methyl)-thiophen-2-ylmethyl ester;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenylmethanesulfonyl]-aceticacid ethyl ester;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzylsulfanyl]-aceticacid ethyl ester;5-[4-(3-Methyl-butylsulfanylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-ethyl-butyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidcyclobutylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidcyclopentylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methyl-pentyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2,4,4-trimethyl-pentyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidcyclohexylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid1,2-dimethyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidcyclopentyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methyl-butyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methylsufanyl-ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-carboxymethylsulfanyl-ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-nitro-furan-2-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidpyridin-2-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-hydroxymethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-methanesulfonyl-benzyl ester;(4-{4-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoylamino]-butyl)phenyl)-aceticacid;(4-{3-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoylamino]-propyl}-phenyl)-aceticacid; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-dimethylaminomethyl-furan-2-ylmethyl ester;(S)-2-Acetylamino-N{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-ethyl}-3-phenyl-propionamide;5-(1H-Indol-5-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;1,1-Dioxo-5-(3,4,5-trimethoxy-benzyl)-1,2,5-thiadiazolidin-3-one;5-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-acetic acid;5-(4-Benzoyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-Naphthalen-2-ylmethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[4-(4-Methyl-pentanoyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-[3-(2-Fluoro-phenoxy)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;3-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-ethoxy}-benzoicacid;1-(3-Methyl-butyl)-6-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-1H-quinolin-2-one;2-Amino-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl benzoic acid4-carboxy-benzyl ester;1,1-Dioxo-5-(3-phenoxy-benzyl)-1,2,5-thiadiazolidin-3-one;3-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;5-(4-Hydroxymethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidmethyl ester; 5-(4-Hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-Nitro-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;5-Amino-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;5-(4-Chloro-3-methoxy-5-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(2-Nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Methyl-2-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;1,1-Dioxo-5-(3-phenyl-propyl)-1,2,5-thiadiazolidin-3-one;5-(4-Butoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;1,1-Dioxo-5-(2-trifluoromethyl-benzyl)-1,2,5-thiadiazolidin-3-one;3-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;4-[5-Amino-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-butyricacid; 5-(2-Methyl-3-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Methyl-3-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(5-Methyl-2-nitro-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(2-Amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-isoindole-1,3-dione;2-[3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-isoindole-1,3-dione;5,5′-[1,4-Phenylenebis(methylene)bis[1,2,5-thiadiazolidine-3-one],1,1-dioxide;N-[2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenyl]-oxalamicacid; 5-(3-Hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid;5-[5-(4-Nitro-phenyl)-furan-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(4-Fluoro-2-trifluoromethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Hydroxymethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Amino-5-hydroxymethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Amino-4-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(2-Amino-3-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Amino-2-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(2-Amino-5-methyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2,2,2-Trifluoro-N-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl]-acetamide;5-(3,4-Dimethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3-Amino-5-hydroxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(3,5-Dimethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;(S)-3-Phenyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzylamino]-propionicacid ethyl ester;(S)-3-Phenyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzylamino]-propionicacid ethyl ester;2-Amino-5-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidmethyl ester;2-Acetylamino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoicacid methyl ester;5-(2-Benzyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-(2,4-Bis-trifluoromethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;1,1-Dioxo-5-(2,4,6-trifluoro-benzyl)-1,2,5-thiadiazolidin-3-one;5-(2-Bromo-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5,5′-[[1,1′-biphenyl]-2,2′-diyl]bis(methylene)bis[1,2,5-thiadiazolidine-3-one],1,1-dioxide;5-(4-Ethylaminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2-Acetylamino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoicacid; 2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoicacid ethyl ester;1,1-Dioxo-5-[4-(phenethylamino-methyl)-benzyl]-1,2,5-thiadiazolidin-3-one;5-(4-Diethylaminomethyl-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidbenzyl ester;N-Benzyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzamide;5-(5-Dimethylaminomethyl-furan-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;N-[2-(3-Trifluoromethyl-phenyl)-ethyl]-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzamide;N-(3-Methyl-butyl)-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzamide;(S)-3-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic acid;(R)-3-Phenyl-2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-propionic acid;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid benzylester; [4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-aceticacid; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidisobutyl ester;2-Amino-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidisobutyl ester;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic acidmethyl ester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoicacid 4-carboxymethoxy-benzyl ester;4-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzylamino]-ethyl}benzoicacid; [4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-aceticacid isobutyl ester;[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-phenoxy]-acetic acidbenzyl ester;N-Isobutyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzamide;5-(5-Diethylaminomethyl-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;3-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidmethyl ester;3-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidethyl ester;3-Nitro-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidisobutyl ester;5-(4-Ethoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;1,1-Dioxo-5-(3-trifluoromethyl-benzyl)-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-carboxymethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid phenethylester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-phenylamino-ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-(3-methoxy-phenyl)ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2,2-dimethyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methoxycarbonyl-2-methyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2,2,4-trimethyl-pentyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-dimethylamino-2,2-dimethyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid(3aR,4S,5R,6aS)-5-benzoyloxy-2-oxo-hexahydro-cyclopenta[b]furan4-ylmethylester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-methyl-4-nitro-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-chloro-4-methyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-ethoxycarbonyl-pentyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-(3-chloro-phenyl)-ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-m-tolyl-ethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-(3-trifluoromethyl-phenyl)-ethyl ester;(R)-3-Phenyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzylamino]-propionicacid ethyl ester;5-[4-(Benzylamino-methyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-methyl-benzyl ester;4-[(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)methyl]-benzoic acid[4-(methoxycarbonyl)-phenyl]methyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-cyclohexyl-2-methyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-phenoxy-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-trifluoromethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-trifluoromethyl-benzyl ester;4-[(1,1,4-trioxido-1,2,5-thiadiazolidin-2-yl)methyl]-benzoic acid2-(4-carboxyphenyl)ethyl ester;3-[[[4-[(1,1,4-Trioxido-1,2,5-thiadiazolidin-2-yl)methyl]benzoyl]-oxy]methyl]benzoicacid;5-[4-(Isobutylamino-methyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;5-{4-[(2,2-Dimethyl-propylamino)-methyl]-benzyl}-1,1-dioxo-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidnaphthalen-1-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-nitro-benzyl ester;(4-{2-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoylamino]-ethyl}-phenyl)-aceticacid; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-nitro-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-(carboxymethyl-amino)-2,2-dimethyl-propyl ester;5-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyloxymethyl]-thiophene-2-carboxylicacid;5-[4-(4-Benzyl-piperazin-1-ylmethyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidbiphenyl-4-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-acetylamino-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-benzyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid2-methyl-3-nitro-benzyl ester; Glycine,N-(aminosulfonyl)-N-[[4-[[(2-phenylethyl)thio]methyl]phenyl]methyl]-,methyl ester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoicacid 3-carboxymethyl-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-methyl-3-nitro-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-fluoro-2-trifluoromethyl-benzyl ester;4-[5-(2,4-Dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoicacid 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-methyl-2-nitro-benzyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid o-tolylester; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid3-(carboxymethyl-methyl-amino)-2,2-dimethyl-propyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid phenylester 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-isobutylcarbamoyl-thiophen-2-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidnaphthalen-2-ylmethyl ester;N,N-Diisobutyl-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzamide;{4-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyl]-piperazin-1-yl}-aceticacid; 4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acidnaphthalen-2-yl ester;5-[4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoyloxymethyl]-thiophene-2-carboxylicacid isobutyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-carbamoyl-thiophen-2-ylmethyl ester;5-[4-(4-Benzyl-piperazine-1-carbonyl)-benzyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-(3-phenyl-propionyl)-thiophen-2-ylmethyl ester;4-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid5-benzylcarbamoyl-thiophen-2-ylmethyl ester;1,1-Dioxo-5-phenyl-1,2,5-thiadiazolidin-3-one;5-(2,4-Diamino-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid methyl ester;3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid;5-(4-Aminomethyl-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;[2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid methylester; [2-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid;5-(2,4-Dimethoxyphenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one potassiumsalt;N-Benzyl-2-[3-methyl-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenoxy]-acetamide;3-[3-Hydroxy-4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-benzyl]-3,4-dihydro-1H-benzo[1,4]diazepine-2,5-dione;5-(4-Iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one;(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid benzyl ester;(S)-2-Amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionicacid;(S)-2-Acetylamino-N{(S)-1-pentylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide;(S)-2-Acetylamino-3-phenyl-N-{(S)-1-(4-phenyl-butylcarbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}propionamide;[4-(2-{(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionylamino}-ethyl)-phenyl]-aceticacid;2-[4-(2-Benzoylamino-2-{1-carbamoyl-2-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethylcarbamoyl}-ethyl)-phenoxy]-malonicacid;(S)-2-(Biphenyl-4-sulfonylamino)-N-pentyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide;(S)-2-(Biphenyl-4-sulfonylamino)-N-(4-phenyl-butyl)-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide;(S)-2-Benzenesulfonylamino-N-pentyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide;(S)-2-Benzenesulfonylamino-N-(4-phenyl-butyl)-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide;(S)-2-Benzenesulfonylamino-N-(3,3-diphenyl-propyl-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionamide;(S)-2-Acetylamino-N-[(S)-2-[3-bromo-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-1-(4-phenyl-butylcarbamoyly)-ethyl]-3-phenyl-propionamide;(S)-2-Benzenesulfonylamino-3-[3-bromo-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-N-(4-phenyl-butyl)-propionamide;(S)-2-((S)-2-Acetylamino-3-phenyl-propionylamino)-3-[3-bromo-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-N-pentyl-propionamide;and(S)-2-Acetylamino-N{(S)-1-pentylcarbamoyl-2-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-ethyl}-3-phenyl-propionamide;or a pharmaceutically acceptable salt thereof; or a prodrug derivativethereof.
 16. A pharmaceutical composition, comprising: a therapeuticallyeffective amount of a compound of claim 1 in combination with one ormore pharmaceutically acceptable carriers.